2012-2013) of the Aichi Cancer Center Research Institute

Aichi Cancer Center Research Institute

Scientific Report 2012 – 2013

Chikusa-ku, Nagoya 464-8681 Japan

(The Cover) The Aichi Cancer Center Research Institute Main Building

Published by Dr. Taira Kinoshita President Aichi Cancer Center Research Institute 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan Telephone: 052-762-6111 Facsimile: 052-763-5233

Editorial Committee Dr. Masahiro Aoki (Division of Molecular Pathology) Dr. Keiichiro Sakuma (Division of Molecular Pathology) Dr. Hiroshi Kumimoto (Central Service Unit) Dr. Malcolm A. Moore, English Editor Ms. Hiromi Tamaki (Director's Office)

Printed by Nagoya University COOP 1 Furoucho, Chikusa-ku, Nagoya 464-0814, Japan

Contents

Preface Taira Kinoshita 1

Organization of the Aichi Cancer Center Research Institute 2

Scientific Reports Division of Epidemiology and Prevention General Summary 5 1. Descriptive epidemiology 1.1. Differences in incidence and trends of hematologic malignancies in Japan and the United States Chihara, D., Ito, H., Matsuda, M., Shibata, A., Katsumi, A., Nakamura, S., Sobue, T.,Morton, LM., Weisenburger, DD., and Matsuo, K. 2. The hospital-based epidemiologic research program at Aichi Cancer Center (HERPACC) study 2.1. Time to first cigarette and upper aerodigestive tract cancer risk in Japan Matsuo, K., Gallus, S., Negri, E., Kawakita, D., Oze, I., Hosono, S., Ito, H., Hatooka, S., Hasegawa, Y., Shinoda, M., Tajima, K., La Vecchia, C., and Tanaka, H. 2.2. Time to first cigarette and lung cancer risk in Japan Ito, H., Gallus, S., Hosono, S., Oze, I., Fukumoto, K., Yatabe, Y., Hida, T., Mitsudomi, T., Negri, E., Yokoi, K., Tajima, K., La Vecchia, C., Tanaka H., and Matsuo K. 2.3. Polymorphisms in base excision repair genes are associated with endometrial cancer risk among postmenopausal Japanese women Hosono, S., Matsuo, K., Ito, H., Hirose, K., Oze, I., Watanabe, M., Nakanishi, T., Tajima, K., and Tanaka, H. 2.4. Coffee and green tea consumption is associated with upper aerodigestive tract cancer in Japan Oze, I., Matsuo, K., Kawakita, D., Hosono, S., Ito, H., Watanabe, M., Hatooka, S., Hasegawa, Y., Shinoda, M., Tajima, K., and Tanaka, H. 3. Tobacco control 3.1. Factors associated with increasing body weight after smoking cessation therapy in Japan Tanaka, H., Taniguchi, C., Oze, I., Saka, H., Ito, H., Tachibana, K., Tokoro, A., Nozaki, Y., Nakamichi, N., Suzuki, Y., and Suehisa, H. 3.2. Cigarette smoke inhalation and lung cancer risk: Case-control study in Japan Fukumoto, K., Ito, H., Park C., Tanaka, H., Matsuo, K., Tajima, K., and Takezaki, T.

Division of Oncological Pathology General Summary 1. Peptide-based non-invasive molecular delivery system by developing novel cancer cell-penetrating peptides (tumor-homing CPPs) for advanced medical

applications Saito, K., Matsushita, M., and Kondo, E 2. Coxsackie and adenovirus receptor – a novel negative regulator of RhoA associated kinase (ROCK) - is a critical regulator of survival and growth of oral squamous carcinoma cells Saito, K., Sakaguchi, M., Iioka, H., Matsui, M., Nakanishi, H., Huh N., and Kondo, E. 3. Anti-tumor impact of p14ARF on gefitinib-resistant non-small cell lung cancers Saito, K., Takigawa, N., Ohtani, N., Iioka, H., Tomita, Y., Ueda, R., Fukuoka, J., Kuwahara, K., Ichihara, E., Kiura, K., and Kondo, E. 4. Lapatinib sensitivities of two novel trastuzumab-resistant HER2 gene-amplified gastric cancer cell lines Oshima, Y., Tanaka, H., Murakami, H., Ito, Y., Furuya, T., Kondo, E., Kodera, Y., and Nakanishi H. 5. LGR5 is a marker of poor prognosis in glioblastoma and is required for survival of brain cancer stem-like cells Nakata, S., Campos, B., Bageritz, J., Bermejo, JL., Becker, N., Engel, F., Acker, T., Momma, S., Herold-Mende, C., Lichter, P., Radlwimmer, B., and Goidts, V.

Division of Molecular Oncology General Summary 1. LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via the Hippo signaling cascade Tanaka, I., Osada, H., Fujii, M., Fukatsu, A., Hida, T., Horio, Y., Kondo, Y., Sato, A., Hasegawa, Y., Tsujimura, T., and Y Sekido 2. RASSF3 downregulation increases malignant phenotypes of non-small cell lung cancer Fukatsu, A., Ishiguro, F., Tanaka, I., Kudo, T., Nakagawa, K., Shinjo, K., Kondo, Y., Fujii, M., Hasegawa, Y., Tomizawa, K., Mitsudomi, T., Osada, H., Hata, Y., Sekido, Y.

Division of Molecular Medicine General Summary 1. Cell cycle deregulation contributes to acute transformation in chronic type adult T-cell leukemia/lymphoma Yoshida, N., Karube, K., Utsunomiya, A., Tsukasaki, K., Imaizumi, Y., Taira, N., Uike, N., Umino, A., Arita, K., Katayama, M., Tsuzuki, S., Kinoshita, T., Ohshima, K., and Seto, M. 2. Generation of mouse models of lymphoid neoplasms using retroviral gene transduction of in vitro-induced germinal center B and T cells Arita, K., Maeda-Kasugai, Y., Ohshima, K., Tsuzuki, S., Katayama, M., Karube, K., Yoshida, N., Sugiyama, T., and Seto, M. 3. Comprehensive gene expression profiles of NK cell neoplasms indicate vorinostat as an effective drug candidate Karube, K., Tsuzuki, S., Yoshida, N., Arita, K., Kato, H., Katayama, M., Ko, YH., Ohshima, K., Nakamura, S., Kinoshita, T., and Seto, M. 4. Clonal heterogeneity of lymphoid malignancies is related to poor prognosis

Katayama, M., Tagawa, H., Nakagawa, M., Fukuhara, N., Sivasundaram, S., Takeuchi, I. , Kasugai, Y., Arita, K., Yoshida, N., Kakiuchi, T., Karube, K., Tsuzuki. S, Nakamura, S., and Seto, M. 5. TEL (ETV6)-AML1 (RUNX1) initiates self-renewing fetal pro-B cells in association with a transcriptional program shared with embryonic stem cells in mice Tsuzuki, S., and Seto, M.

Division of Immunology General Summary 1. Constitutively active autophagy causes a CTL epitope generation in pancreatic cancer cells Demachi-Okamura, A., and Kuzushima, K. 2. Construction and molecular characterization of a T-cell receptor-like antibody and CAR-T cells specific for minor histocompatibility antigen HA-1H Akatsuka, Y., Inaguma, Y., Akahori, Y., Murayama, Y., Shiraishi, K., Endoh, A., Demachi-Okamura, A., Hiramatsu, K., Nishimura, Y., Takahashi, To., Emi, N., and Kuzushima, K. 3. Pluripotent stem cell-derived proliferating myeloid cells as a possible basis for cellular vaccine cancer immunotherapy Zhang, R., Liu, T., Maki, H., Kuzushima, K., and Uemura, Y. 4. Modification of IL-12p70/osteopontin balance in dendritic cells by ligand activation of invariant NKT cells Zhang, R., Liu, T., Kuzushima, K., and Uemura, Y.

Division of Virology General Summary 1. Interaction between Basic Residues of Epstein-Barr Virus EBNA1 Protein and Cellular Chromatin Mediates Viral Plasmid Maintenance Kanda, T. and Tsurumi, T. 2. Contribution of Myocyte Enhancer Factor 2 (MEF2) Family Transcription Factors to BZLF1 Expression in Epstein-Barr virus Reactivation from Latency Murata, T. and Tsurumi, T. 3. Heat shock protein 90 inhibitors repress latent membrane protein 1 (LMP1) expression and proliferation of Epstein-Barr virus-positive natural killer cell lymphoma cells Murata, T. and Tsurumi, T. 4. Different Distributions of Epstein-Barr Virus Early and Late Gene Transcripts within Viral Replication Compartments Sugimoto, A., Sato, Y., Murata, T., Kanda, T., and Tsurumi, T. 5. Nuclear Transport of Epstein-Barr Virus DNA Polymerase is Dependent on the BMRF1 Polymerase Processivity Factor and Molecular Chaperone Hsp90 Kawashima, D., Murata, T., Kanda, T., and Tsurumi T. 6. Epstein-Barr Virus Deubiquitinase Downregulates TRAF6-mediated NF-κB Signaling during Productive Replication Saito, S., Murata, T., Kanda, T., and Tsurumi, T.

iii

7. Pin1 Interacts with the Epstein-Barr Virus DNA Polymerase Catalytic Subunit and Regulates Viral DNA Replication Narita, Y., Murata, T., Kanda, T., and Tsurumi, T. 8. HLA-restricted Presentation of WT1 Tumor Antigen in B-lymphoblastoid Cell Lines Established using a Maxi-EBV System Kanda, T., Kuzushima, K., and Tsurumi, T. 9. Epigenetic Histone Modification of the Epstein-Barr Virus BZLF1 Promoter during Latency and Reactivation in Raji Cells Murata, T., Kondo, Y., and Tsurumi, T.

Division of Molecular Pathology General Summary 1. c-Myc and CDX2 mediate E-selectin ligand glycan expression in colon cancer cells undergoing EMT Sakuma, K., Kannagi, R., and Aoki, M. 2. CDX Transcription Factors Positively Regulate Expression of PLEKHG1 in Intestinal Epithelium Aoki, M., Fujishita, T., and Taketo, MM. 3. Roles of the mTOR signaling in intestinal adenocarcinoma formation in cis-Apc/Smad4 mutant mice Fujishita, T., Taketo, MM., and Aoki, M.

Division of Biochemistry General Summary 1. Emerging roles of ubiquitin-proteasome machinery in formation of primary cilia Kasahara, K., Era, S., Kawamoto, E., Kawakami, Y., Kiyono, T., Kawamura, Y., Goshima, N., and Inagaki, M. 2. Cytokinetic failure induces aneuploidy and aging in vimentin phosphorylation deficient mice Tanaka, Hir., Matsuyama, M., Inoko, A., Goto, H., Yonemura, S., Kobori, K., Tanigawa, N., Hayashi, Y., Kondo, E., Itohara, S., Izawa, I. and Inagaki, M. 3. Perspective of Aurora A kinase as a therapeutic target for cancer Goto, H., Watanabe, N., Kobori, K., Inoko, A., Mochizuki, H., Togashi, T., Kisu, Y., Kawamura, Y., Kawakami, Y., Goshima, N., and Inagaki, M. 4. Novel cell cycle regulation through centrosomes Inoko, A., Inaba, H., He, D., Goto, H., Hayashi, Y., Izawa, I., Urano, T., Yonemura, S., Kiyono, T., Goshima, N., and Inagaki, M. 5. Interaction of Cell Polarity Regulator Scribble with Multidrug Resistance Protein 4 (MRP4/ABCC4) Izawa, I., Hayashi, Y., and Inagaki, M.

Division of Epigenomics General Summary 1. The PRC2 chromatin regulator is a key regulator of epigenetic plasticity

in glioblastoma Natsume, A., Ito, M., Katsushima, K., Ohka, F., Hatanaka, A., Shinjo, K., Sato, S., Takahashi, S., Ishikawa, Y., Takeuchi, I., Shimogawa, H., Uesugi, M., Okano, H., Kim, SU., Wakabayashi, T., Issa, JP., Sekido, Y., and Kondo, Y. 2. Hepatitis Virus Infection Affects DNA Methylation in Mice with Humanized Livers. Okamoto Y, Shinjo K, Shimizu Y, Sano T, Yamao K, Gao W, Fujii M, Osada H, Sekido Y, Murakami S, Tanaka Y, Joh T, Sato S, Takahashi S, Wakita T, Zhu J, Issa JP, and Kondo Y.

Central Service Unit General Summary 1. Relationship between risk of esophageal cancer and the number of polymorphisms in mitochondrial DNA Kumimoto, H.

Librarians T. Yasuda, T. Shibata, T. Matsunaga, M. Sakou, and N. Terashima

Publications 1. Journals 2. Reviews and books 3. Abstracts for international conferences

Records of seminars

Author index for research reports and publications

From left to right Ms. H. Tamaki and Dr. T. Kinoshita Inset: Dr. K. Tajima

Preface ______

It is my pleasure to share with you the 23rd Scientific Report (2012-2013) of the Aichi Cancer Center Research Institute. Since its establishment in 1964, Scientific Reports have been published biennially to document major research activities and highlight progress in and contributions to cancer research worldwide. As illustrated on the following pages, the Research Institute consists of 8 Divisions, along with a Central Service Unit, an Animal Facility and a Laboratory of Translational Research, with overall research emphasis on three areas: cancer prevention/epidemiology; preclinical/experimental therapy; and carcinogenesis/molecular biology. In addition, the institute is affiliated with the Nagoya University Graduate School of Medicine and the Nagoya City University Graduate School of Pharmaceutical Sciences. At the present time 7 professors and 4 associated professors nominated from chiefs and section heads of the Research Institute are engaged in education of graduate school students at the two universities. In Aichi Cancer Center Research Institute itself, a total of 76 staff members, 42 researchers and 18 research assistants, as well as 16 research residents, are now conducting a wide range of studies, together with 8 graduate school students, and approximately 25 visiting research fellows and 40 temporary research assistants.

The major areas being pursued are as follows: - descriptive and analytical epidemiology of cancers - primary and secondary prevention of cancer - molecular pathogenesis of intractable malignancies - peptide-based anti-cancer DDS technology - molecular oncology of respiratory tract cancer - molecular biology of translocation-junction genes in hematopoietic tumors - basic studies for cancer immunotherapy - oncogenicity, molecular biology and immunology of DNA tumor viruses - glycobiology of cancer cells in relation to metastasis - genetic dissection of signaling pathways in colon cancer - molecular mechanisms of cell proliferation and movement - involvement of repair mechanisms in carcinogenesis

More detailed descriptions of the individual research topics of each Division appear in the contents of this report. It is our sincere hope that the activities of the Institute will make a major contribution to elucidation of the mechanisms of carcinogenesis and to development of novel clinical applications in cancer diagnosis, treatment and prevention. Finally, I would like to express my deep appreciation to the Aichi Prefectural Government for the continuous support received since this Institute was founded in 1964. Granting support from the Ministry of Education, Science, Sports, Culture and Technology, the Ministry of Health, Labor, and Welfare, the Ministry of Economy, Trade and Industry, Japan, and other related organizations, is also gratefully acknowledged.

January, 2014

Taira Kinoshita, M.D., M.P.H., D.M.Sci. Acting Director, President

Organization of the Aichi Cancer Center Research Institute ______

SCIENTIFIC REPORTS

From left to right First row: Dr. I. Oze, Dr. H. Ito, Dr. K. Matsuo, Dr. H. Tanaka, Dr. S. Hosono, Ms. M. Watanabe Second row: Ms. Y. Yamauchi, Ms. K. Fukaya, Ms. A. Yoshida, Ms. S. Inui, Ms. A. Uematsu, Ms. M. Miyoshi, Ms. Y. Matsubara, Ms. T. Ito Third row: Dr. K. Ishioka, Ms. S. Torii, Ms. Y. Tanaka, Ms. T. Nishiwaki, Ms. S. Irikura, Ms. R. Saito, Ms. Y. Mano Fourth row: Dr. M. Nakao, Dr. K. Fukumoto, Dr. D. Chihara, Ms. I. Kato, Ms. S. Nimura, Ms. M. Yamaguchi, Ms. A. Hiraiwa, Ms. Y. Hamajima, Ms. K. Sugamuma

______Division of Epidemiology and Prevention______

Hideo Tanaka, M.D., PhD. Chief Keitaro Matsuo, M.D., PhD., S.M. Section Head (until June 2013) Hidemi Ito, M.D., PhD., M.P.H. Section Head (as of April 2009) Satoyo Hosono, M.D., PhD. Senior Researcher (as of April 2009) Isao Oze, M.D. Senior Researcher (as of April 2012) Daisuke Kawakita, M.D. Research Resident (until March 2012) Makoto Nakao, M.D. Research Resident (until March 2013) Koichi Fukumoto, M.D. Research Resident (as of April 2012) Dai Chihara, M.D., PhD. Research Resident (as of April 2013) Miki Watanabe, MSc. Research Assistant (as of April 2006) Misako Nakahama. Research Assistant (until March 2012) Tomoko Ito. Research Assistant (as of April 2012)

Yasuo Morishima, M.D. PhD. Researcher (as of April 2011) Keitaro Matsuo, M.D., PhD., S.M. Researcher (as of July 2013)

Visiting Trainees Kiyonori Kuriki, B.P., D.M.Sc. University of Shizuoka Takakazu Kawase, M.D., PhD. Fred Hutchinson Cancer Research Center. Daisuke Kawakita, M.D., PhD. Nagoya City University Hideo Nakane, PhD. Toyota Central R&D Labs., Inc. Masao Nishira, M.D. Nagoya University Graduate School of Medicine. Tania Islam, M.D. Nagoya University Graduate School of Medicine. Dai Chihara, M.D. Nagoya University Graduate School of Medicine. Aiko Sueta, M.D. Kumamoto University Graduate School of Medicine. Makiko Higashi, M.D. Nagoya University Graduate School of Medicine. Koichi Fukumoto, M.D. Nagoya University Graduate School of Medicine. Kuka Ishioka, M.D. Nagoya University Graduate School of Medicine. Chie Taniguchi. Nagoya Medical Center.

General Summary The current research activities of the Division of Epidemiology and Prevention cover the following three major subjects: (1) descriptive epidemiology of cancer incidence, mortality and survival using data from the Aichi Prefectural Cancer Registry and other population-based registries in collaborative studies; (2) analytical epidemiology based on the hospital-based epidemiologic research program at Aichi Cancer Center (HERPACC) to determine risk and protective factors for cancer, with a particular focus on gene-environmental interactions; and (3) epidemiologic studies for tobacco control.

Our main findings in 2012 and 2013 were that: 1) in a comparative study of incidence in hematologic malignancies between Japan and the United States from 1993-2008, the age-adjusted incidence in Japan was approximately one-half that in the US but has been increasing significantly, whereas no significant change was seen in the US; 2) nicotine dependence, as indicated by the time to first cigarette (TTFC) of the day, is associated with an increased risk of upper aerodigestive tract and lung cancers; 3) polymorphisms in base excision repair genes (XRCC1 and haplotype TG) are associated with endometrial cancer risk among postmenopausal Japanese women; 4) coffee intake might be linked with a decreased risk of upper aerodigestive tract cancer, whereas that of green tea might confer an increased risk; 5) younger age, non-varenicline use, presence of a comorbidity with nicotine dependence, high FTND scores and success of quitting smoking were significantly associated with weight gain among persons who received smoking cessation therapy in Japan; and 6) inhalation of cigarette smoke is an independent risk factor for lung cancer after adjustment for pack-years of smoking in the Japanese population.

1. Descriptive epidemiology National Cancer Institute, NIH, DHHS, Rockville, MD, USA 6 1.1 Differences in incidence and trends of * Department of Pathology, City of Hope National hematologic malignancies in Japan and Medical Center, Duarte, CA, USA *7 Department of Preventive Medicine, Kyushu the United States 1 1 University Faculty of Medical Science, Fukuoka, Japan Chihara, D., Ito, H., Matsuda, M.* , Shibata, A.* , Katsumi, A.*2, Nakamura, S.*3, Sobue, T.*4, Morton, LM.*5, Weisenburger, DD.*6, Matsuo, K.*7 The incidence of a malignant disease reflects genetics and cumulative exposure to factors in the living environment of any particular population. Therefore, evaluation of incidences and trends of disease in different populations may provide insights into its etiology and pathogenesis. With a focus on hematologic malignancies according to specific subtypes, we used population-based registry data in Japan (N=125,148) and the United States (US; N=172,925) from 1993 to 2008. Overall age-standardized incidence rates for all hematologic Fig. 1. Incidences and trends for haematological malignancies per 100,000 in 2008 were 18.0 for malignancies from 1993 to 2008 in Japan (in blue) males and 12.2 for females in Japan, and 34.9 for and the US (in red). Circles indicate the observed males and 23.6 for females in the US. The age-standardized incidence rates of males and age-adjusted incidence of hematologic females combined, and lines indicate the malignancies in Japan was approximately one-half age-standardized incidence rates estimated by Joinpoint regression analysis. The axis denotes that in the US but has been increasing significantly, the annual incidence /100,000. whereas no significant change was seen in the US {annual percent change (95%CIs): Japan, +2.4% (1.7, 3.1); US, +0.1% (-0.1, 0.2)}. The most 2. The hospital-based epidemiologic re- frequent hematologic malignancy in both countries search program at Aichi Cancer Center is NHL, accounting for 39.6% of all hematologic (HERPACC) study malignancies in Japan and 54.5% in the US. The lowest incidence was seen for CML, with 2.1 Time to first cigarette and upper respective figures of 3.4% and 3.0%. The aerodigestive tract cancer risk in Japan Matsuo, K., Gallus, S.*1, Negri, E.*1, Kawakita, D., Oze, incidences of lymphoid malignancies such as HL, *2 *3 NHL and MM showed marked differences between I., Hosono, S., Ito, H., Hatooka, S. , Hasegawa, Y. , Shinoda, M.*4, Tajima, K.*5, La Vecchia, C.*1, 6, Tanaka, the US and Japan, whereas those for AML, ALL, H. and CML were less pronounced (Figure 1). HL and Cigarette smoking is the major cause for upper NHL are increasing substantially in Japan but not in aerodigestive tract (UADT) cancers. The time to the US, suggesting that environmental influences, first cigarette (TTFC) of the day is a distinct such as Westernization of the life style, may be indicator of nicotine dependence, but scanty causing this increase. Differences in the incidence information is available on its possible relation with and trends for specific subtypes also showed a UADT cancers (oral, oropharyngeal, marked contrast across subtypes which, in turn, hypopharyngeal, laryngeal, nasopharyngeal, and may provide significant new insights into disease esophageal). etiology in the future. This case-control study included a total of 1,009

1 incident UADT cancer cases and 3,027 age- and * Surveillance Division, Center for Cancer Control and sex-matched noncancer controls admitted to the Information Services, National Cancer Center, Japan. *2 Department of Clinical Oncology, Hamamatsu Aichi Cancer Center (Nagoya, Japan) between 2001 University School of Medicine, Hamamatsu, Japan and 2005. We estimated OR and 95% confidence *3 Department of Pathology, Nagoya University intervals (CI) for TTFC using logistic regression Graduate School of Medicine, Nagoya, Japan. models after adjustment for several potential *4 Department of Environmental Medicine and confounders. Population Science, Osaka University Graduate School TTFC was inversely related to the risk of of Medicine, Osaka, Japan UADT cancer, and this association was consistent 5 * Division of Cancer Epidemiology and Genetics, across subtypes of head and neck cancer and

Table 1. Associations between TTFC and UADT cancers among ever- and current smokers stratified by subsite. (Footnote: ORs were calculated by unconditional logistic regression adjusted for smoking status, duration of smoking, cigarettes per day, alcohol consumption, fruit and vegetable intake, and SES.) esophageal cancer. For all UADT cancers This case-control study included a total of 1,572 considered among ever smokers and after accurate incident LC cases and 1,572 non-cancer controls allowance for smoking quantity and duration, visiting for the first time the Aichi Cancer Center besides other relevant covariates, compared with Hospital between 2001 and 2005. We estimated the TTFC more than 60 minutes, the adjusted ORs were odds ratio (OR) and 95% confidence intervals (CI) 1.40 (95% CI: 0.93-2.11) for 31 to 60 minutes, 1.76 for TTFC using a logistic regression model after (95% CI: 1.20-2.58) for 6 to 30 minutes, and 2.43 adjustment for several potential confounders. (95% CI: 1.64-3.61) for within 5 minutes. No TTFC was inversely associated with the risk of significant heterogeneity was found in strata of sex, LC. This association was consistent across age, alcohol consumption, fruit and vegetable histological subtypes of LC. For all LCs considered intake, and occupation for overall and site-specific among ever smokers and after accurate allowance analysis. for smoking quantity and duration, besides other Nicotine dependence, as indicated by the TTFC, relevant covariates, compared with TTFC >60 min, is associated with increased risk of UADT cancers the adjusted ORs were 1.08 (95% CI, 0.73-1.61) for and is therefore an independent marker of exposure TTFC of 31-60 min, 1.40 (0.98-2.01) for 6-30 min to smoking. Our result points to more detailed risk and 1.86 (1.28-2.71) for within 5 min (Ptrend, < evaluation of UADT cancers allowed by the TTFC. 0.001). Statistically marginally significant heterogeneity by histological subtype was observed 1 * Department of Epidemiology, Istituto di Ricerche (Pheterogeneity, 0.002). Farmacologiche ‘Mario Negri’, Milan, Italy Nicotine dependence, as indicated by the TTFC, 2 * Respiratory Surgery, Aichi Cancer Center Central is associated with increased risk of LC and is Hospital 3 therefore can be considered an independent marker * Head/Neck Surgery, Aichi Cancer Center Central of exposure to tobacco smoking. Hospital 4 * Aichi Cancer Center Central Hospital 1 *5 Aichi Cancer Center Research Institute * Department of Epidemiology, Istituto di Ricerche 6 Farmacologiche ‘Mario Negri’, Milan, Italy * Department of Clinical Medicine and Community 2 Health, Universitá degli Studi di Milan, Milan, Italy * Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Central Hospital *3 Department of Thoracic Oncology, Aichi Cancer 2.2. Time to first cigarette and lung cancer Center Central Hospital risk in Japan *4 Department of Surgery, Division of Thoracic Surgery, *1 Ito, H., Gallus, S. , Hosono, S., Oze, I., Fukumoto, K., Kinki University Faculty of Medicine, Osaka-Sayama *2 *3 *4 *1 Yatabe, Y. , Hida, T. , Mitsudomi, T. , Negri, E. , *5 Department of Thoracic Surgery, Nagoya University *5 *6 *1,7 Yokoi, K. , Tajima, K. , La Vecchia, C. , Tanaka H., Graduate School of Medicine, Nagoya Matsuo K. *6 Aichi Cancer Center Research Institute Cigarette smoking is the major cause of lung *7 Department of Clinical Medicine and Community cancer (LC). Although the time to first cigarette Health, Universitá degli Studi di Milan, Milan, Italy (TTFC) of the day is a distinct indicator of nicotine dependence, little information is available on its possible relation to LC. 7

Table 2. Associations between FTTC and lung cancers (LCs) among ever and current smokers stratified by histologic subtypes. (Footnote: ORs were calculated by an unconditional logistic regression model adjusted for age, alcohol consumption, fruit and vegetable intake and socioeconomic status. Heterogeneity testing was carried out by likelihood-ratio test after estimations by an unconditional logistic regression model adjusted for age, sex, CPD, duration of smoking, smoking status, alcohol consumption, fruit and vegetable intake and occupation, except for a stratifying factor).

2.3. Polymorphisms in base excision (BMI) ≥ 25) and rs25487. The XRCC1 repair genes are associated with polymorphisms were in complete linkage endometrial cancer risk among disequilibrium, and the XRCC1 TG haplotype was postmenopausal Japanese women significantly associated with endometrial cancer Hosono, S., Matsuo, K.*1, Ito, H., Hirose, K.*2, Oze, I., risk. The interaction between the CA haplotype and 3 4 Watanabe, M., Nakanishi, T.* , Tajima, K.* , Tanaka, BMI was marginally significant, whereas that 1 H.* between haplotype in XRCC1 and rs1136410 Objectives: Polymorphisms in base excision (PARP1) was not significant. repair (BER) genes are associated with risk for Conclusion: We found a significant association several types of cancers but have not been studied between endometrial cancer risk and XRCC1 with respect to endometrial cancer among Japanese. polymorphisms and the TG haplotype in Therefore, we conducted a case-control study to postmenopausal Japanese women. explore the association between polymorphisms in base excision repair (BER) genes and the risk of *1 Department of Epidemiology, Nagoya University endometrial cancer. Graduate School of Medicine Methods/materials: This study included a total *2 Department of Planning and Information, Aichi of 91 postmenopausal subjects with endometrial Prefectural Institute of Public Health cancer and 261 non-cancer controls who visited *3 Department of Gynecologic Oncology, Aichi Cancer Center Hospital Aichi Cancer Center between 2001 and 2005. We 4 focused on single nucleotide polymorphisms * Aichi Cancer Center Research Institute (SNPs) within coding regions of five BER genes (OGG1, MUTYH, XRCC1, APEX1, PARP1). To 2.4. Coffee and green tea consumption is assess lifestyle factors in the etiology of associated with upper aerodigestive endometrial cancer, we used a self-administered tract cancer in Japan *1 *2 questionnaire. Associations were evaluated using Oze, I., Matsuo, K. , Kawakita, D. , Hosono, S., Ito, H., Watanabe, M., Hatooka, S.*3, Hasegawa, Y.*4, Shinoda, multivariate unconditional logistic regression *5 *6 models. We also assessed whether there were M. , Tajima, K. , Tanaka, H. The impact of coffee and green tea consumption intergenic associations or any interaction with on upper aerodigestive tract (UADT) cancer risk obesity. has not been established in detail. Evaluation of the Results: We observed a significant association possible anti-carcinogenic properties of their between endometrial cancer risk and XRCC1 ingredients is confounded by the potential increase rs1799782 (C>T, Arg194Trp) and XRCC1 rs25487 in risk due to the high temperatures at which these (G>A, Arg399Gln), also uncovering a significant beverages are generally consumed. We conducted a association between obesity (Body mass index case-control study to evaluate the association

8 between coffee and tea consumption and the risk of between the first visit of SCT and 12 months after UADT cancer. The study enrolled 961 patients with the end of SCT. They were recruited from six UADT cancer and 2,883 non-cancer outpatients hospitals between 2008 and 2011. We collected who visited Aichi Cancer Center between 2001 and demographic information and presence of a 2005. Information on coffee and green tea comorbidity with nicotine dependence, as well as consumption and other lifestyle factors was smoking history and the Brinkman Index obtained collected via a self-administered questionnaire. using self-report questionnaires at the first session. Consumption of 3 or more cups of coffee per day The subjects were followed up at 3, 6 and 12 had a significant inverse association with UADT months after the end of SCT, to obtain data on body cancer (OR 0.73, 95% CI 0.55-0.96). In contrast, weight and smoking status using a mail-based consumption of three or more cups of green tea per self-reported questionnaire. Risk of weight gain of day had a significant positive association (OR 1.39, +3.5 kg was assessed by stepwise logistic 95% CI 1.13-1.70). These links were evident for regression analysis. head and neck cancer but not for esophageal cancer. Age 50 yr and over (OR, 0.38, 95%CI: The association of coffee consumption with head 0.19-0.76) and varenicline use (OR, 0.30, 95%CI: and neck cancer was observed only among never 0.11-0.78) were significantly associated with low smokers and alcohol drinkers. Similarly, the risk of weight gain. The presence of a comorbidity association of green tea consumption was observed with nicotine dependence (OR, 3.33, 95%CI: among never smokers and never alcohol drinkers. 1.10-10.00), high level of nicotine dependence at No change was seen on stratification for baseline (OR, 2.07, 95%CI: 1.09-3.92) and success confounding factors. These findings suggest that of quit smoking at 12 months after the end of SCT consumption of coffee might be associated with a (OR, 4.57, 95%CI: 1.94-10.08) were significantly decreased risk of UADT cancer, whereas that of associated with weight gain. green tea might confer increased risk. Our study showed that younger age, non-varenicline use, presence of a comorbidity with *1 Department of Preventive Medicine, Kyushu nicotine dependence, high FTND scores and University Graduate School of Medicine success in quitting smoking were significantly *2 Department of Otorhinolaryngology, Head and Neck associated with weight gain among persons who Surgery, Nagoya City University Graduate School of received SCT in Japan. Medical Sciences *3 Department of Respiratory Surgery, Ichinomiya Nishi *1 Hospital National Hospital Organization Nagoya Medical *4 Center Department of Head/Neck Surgery, Aichi Cancer *2 Center Hospital National Hospital Organization Kinki-Chuo Chest *5 Department of Thoracic Surgery, Aichi Cancer Center Medical Center *3 Social Insurance Chukyo Hospital Hospital *4 *6 Kitasato University Kitasato Institute Hospital Department of Public Health and Occupational *5 Medicine, Mie University Graduate School of Medicine National Hospital Organization Shikoku Cancer Center

3. Tobacco control 3.2. Cigarette smoke inhalation and lung cancer risk: Case-control study in 3.1. Factors associated with increasing Japan Fukumoto, K., Ito, H., Park C., Tanaka, H., Matsuo, K.*1, body weight after smoking cessation Tajima, K.*2, Takezaki, T.*3 therapy in Japan *1 *1 Several epidemiologic studies have Tanaka, H., Taniguchi, C. , Oze, I., Saka, H. , Ito, H., Tachibana, K.*2, Tokoro, A.*2, Nozaki, Y.*3, Nakamichi, demonstrated that degree of cigarette smoke N.*3, Suzuki, Y.*4, Suehisa, H.*5 inhalation is associated with the risk of lung cancer Post-cessation weight gain possibly attenuates (LC) in European population. However, to date, motivation to engage or sustain a smoking quit there have been few such studies in Asian attempt that induces poorer cessation outcomes. populations. Our aim was to clarify the relationship Weight control intervention in patients who attempt between cigarette smoke inhalation and the risk of to quit the habit is therefore an important issue. We LC in Japanese. aimed to identify factors associated with weight We therefore conducted a case-control study of gain in smokers who received smoking cessation cigarette smoking and LC risk in Aichi Prefecture. therapy (SCT) in Japan. Between 1993 and 1998, several hospitals recruited We observed weight change in 283 smokers newly diagnosed incident patients with histologically confirmed LC (n=653). The case 9 eligibility included an age of 20–81 years, no even after adjustment for pack-years in the Japanese previous diagnosis of lung, or other cancer, and an population. Cigarette smoke inhalation might have ability to participate and provide informed consent. an additive effect toward LC risk. The study included both hospital controls (HC: n=453) and community-based controls (CC: n=828). *1 Department of Preventive Medicine, Kyushu The eligibility criteria for the two control groups University Faculty of Medical Science *2 were the same as for cases except that the hospital Department of Public Health & Occupational Medicine, Mie University Graduate School of Medicine controls were admitted for non-malignant diseases *3 or conditions unrelated to cigarette smoking. Odds Department of Island and Community Medicine, Kagoshima University Graduate School of Medical and ratios (OR) and 95% confidence intervals (CI) were Dental Sciences derived from unconditional logistic regression analysis, adjusted for basic confounding variables such as age, sex, drinking status, family history of LC, occupation, and years of education. The mean of age was 60.7 in cases and 60.1 in controls. Cases had a higher proportion of males, individuals having a family history of LC, heavy drinkers, and current smokers. The most common histologic types of LC were adenocarcinoma (AD) (50.9%), squamous cell carcinoma (SQ) (22.1%) and small cell carcinoma (SM) (19.2%). Compared to ever smokers in controls, those in cases started Fig. 2. Association between cigarette smoking at younger age, smoked more cigarettes smoke inhalation and lung cancer risk in per day and had smoked for a longer duration. The ever smokers proportion of smokers who inhaled cigarette smoke was greater in cases. The risk of LC in ever smokers was significantly higher than never smokers, especially in smokers who inhaled. Compared with never smokers, ORs for ever smokers who do not inhale cigarette smoke (inhale-no) and ever smokers who inhale cigarette smoke (inhale-yes) were 1.72 (95%CI: 1.15-2.59) and 3.28 (95%CI: 2.38-4.53), when adjusted for basic confounding variables. Stratified analyses by histologic types of LC showed that these associations were quite strong in SQ and SM (inhale-no: OR 10.1(95%CI: 4.96-20.7), inhale-yes: OR 19.7 (95%CI: 10.3-37.6)) On the other hand, such associations seemed to be mild in AD (inhale-no: OR 0.87(95%CI: 0.51-1.48), inhale-yes: OR 1.50(95%CI: 1.01-2.21)). Stratified analysis by pack-year showed that the OR of the “inhale-yes” group was higher than for the “inhale-no” group in every category of pack-years (<20, 20-39, 40-59, 60 or more). When the analysis was restricted to ever smokers, the OR (adjusted for basic confounding factors and pack-year) of LC risk in ever smokers who inhaled cigarette smoke was significantly higher than who did not. OR for “inhale-yes” group compared with “inhale-no” group was 1.52 (95%CI: 1.06-2.18, p=0.021). No heterogeneity was observed across histologic types of LC. Our case-control study demonstrated that inhalation of cigarette smoke is an independent risk for LC

From left to right First row: Dr. Ken Saito, Dr. Akiko Yusa, Dr. Eisaku Kondo, Dr. Hayao Nakanishi, Dr. Susumu Nakata, Second row: Ms. Noriko Saito, Ms. Mayumi Yoshimura, Ms. Yumi Matsumoto, Ms. Risayo Watanabe Third row: Dr. Makoto Toneri, Dr. Hidekazu Iioka, Dr. Daisuke Yamashita, Dr. Takuya Saito,

______Division of Oncological Pathology ______

Eisaku Kondo, M.D., Chief Hayao Nakanishi, M.D., Section Head Susumu Nakata, M.D., Senior Researcher Keiko Shinjo, M.D., Senior Researcher Ken Saito, Ph.D., Researcher Daisuke Yamashita, M.D., Research Resident (as of April 2013) Noriko Saito, Research Assistant Mayumi Yoshimura, Semi-regular Employee Keiko Nishida, Semi-regular Employee Risayo Watanabe, Semi-regular Employee (as of February 2013) Yuko Saito, Semi-regular Employee (until December 2012) Junya Yamamoto, Semi-regular Employee (until December 2012)

Visiting Trainees Hidekazu Iioka, Ph.D., Laboratory of Bioregulatory Science, Advanced Medical Research Center, Aichi Medical University (as of May 2012) Akiko Yusa, Ph.D., Knowledge Hub Aichi, Priority Research Projects, Aichi Science & Technology Foundation Shinichiro Maseki, M.D., Dept. of Otorhinolaryngology, Konan Kosei Hospital Takuya Saito, M.D., Dept. of Surgery, Pref. Osaka Saiseikai Izuo Hospital Akihiro Ito, Dep. of Pharmacology, Konan Kosei Hospital Tomomi Furuya, Graduate School of Pharmaceutical Sciences, Meijo University (until September 2013) Kayoko Terazawa, Graduate School of Pharmaceutical Sciences, Meijo University (as of February 2013) Yumi Matsumoto, Dept. Micro-Nano Systems Engineering, Graduate School of Engineering, Nagoya University (as of May 2013) Makoto Toneri, M.D., Dept. Anesthesia, Aichi Cancer Center Hospital (as of October 2012)

General Summary The aim for our research at the Division of Oncological Pathology is to disclose the pathogenesis of human malignancies, especially focusing on intractable tumors such as advanced staged cancers of gastrointestinal tract, oral, head and neck cancers, lung cancers, brain tumors, aggressive leukemias and so on, through molecular analyses based on the data obtained by morphological and biological examination of cancer tissues and human cancer cells. Our interest is now concretely concentrating on finding novel therapeutic targets through basic pathological research for molecular analysis of progression, metastasis, invasion, and stem cell pathology. As a second important aim, we are also making effort to develop advanced antitumor medical technologies for clinical application. In addition to these molecular pathological research activities, another important responsibility of our division is an autopsy service, which provides a basis with implications and providing motivation for new research activity. Postmortem examinations give us valuable information on the behavior of neoplasms and their response to therapy, helping clarify pathogenesis of cancers. Thus, the present aim of our division is promoting comprehensive pathological research and contributing to current and near-future tumor medicine.

1. Peptide-based non-invasive molecular drugs such as small molecule inhibitors, chimeric delivery system by developing novel cancer antibodies and siRNAs. However, in tumor cell-penetrating peptides (tumor-homing medicine, efficient drug delivery systems that CPPs) for advanced medical applications enable specific targeting of tumors and minimize Saito, K., Matsushita, M.*1, and Kondo, E. side effects have yet to be fully developed. We are Molecular targeting medicine has been recently now focusing on establishing peptide-based DDS supported by introduction of various anticancer with novel cell-penetrating peptides (CPPs), which

consequent morphological reaction appears reminiscent of anoikis, rather than epithelial-mesenchymal transition (EMT), and the dissociation of oral SCC cells was triggered not by lack of contact with extracellular matrix (ECM), but Fig. 1. Unique biological characteristics of CPPs as peptides (left). In by loss of cell-to-cell contact vivo tumor detection by administration of novel tumor-homing CPPs (right). caused by abnormal translocation This report was published in Nature Commun., 3:951-963, July17, 2012. of E-cadherin from surface membranes to cytoplasm. are highly absorbable by human tumor cells, such Immunoprecipitation assays of the peptides having non-invasive properties in vivo. CAR-transfected oral SCC cell line, HSC-2, with or Recently we generated tumor-lineage-homing CPPs without ROCK inhibitor (Y-27632), revealed that that are highly permeable to cancer cells according CAR directly associates with ROCKI and ROCKII, to their tumor origins by employing a specific resulting in inhibition of ROCK activity and random peptide library. These CPPs are encoded by contributing to maintenence of cell-to-cell adhesion a novel artificial amino acid sequence and differ for growth and survival. Based on these findings, in from conventional CPPs such as TAT, pAnt vivo behavior of CAR-downregulated HSC-2 cells (antennapedia), and HIV gp41. For example, we from siRNA knockdown was compared with that of obtained a CPP readily penetrating cells derived normally CAR-expressing cells in intraperitoneally from colon adenocarcinomas, as well as examples xenografted mouse models. We found that the mice for human leukemia and hepatocellular carcinoma engrafted with CAR siRNA-pretreated HSC-2 cells cells. These tumor-lineage-homing CPPs should showed poor formation of metastatic foci in find application in peptide-based non-invasive contrast to those implanted with control medical technologies such as anti-cancer siRNA-pretreated cells that maintained endogenous therapeutics and diagnostic imaging. CAR expression and that disseminated extensive peritoneal lesions. Thus, CAR substantially impacts *1 Department of Molecular and Cellular Physiology, on growth and survival of oral SCC cells through Graduate School of Medicine, University of the Ryukyus specific interactions with ROCK in vitro and in vivo, providing clues for the molecular therapy or head 2. Coxsackie and adenovirus receptor – a and neck SCCs. novel negative regulator of RhoA associated kinase (ROCK) - is a critical *1 Department of Cell Biology, Graduate School of regulator of survival and growth of oral Medicine, Dentistry and Pharmaceutical Sciences, squamous carcinoma cells Okayama University Saito, K., Sakaguchi, M.*1, Iioka, H., Matsui, M., *1 Nakanishi, H., Huh N. , and Kondo, E. Coxsackie and adenovirus receptor (CAR) is essential for adenovirus infection to target cells. Constitutive expression in various cancerous and normal tissues has been reported and recently the biological role of CAR in human cancers of several different origins has been investigated with respect to tumor progression, metastasis and tumorigenesis. However, its biological functions in tumor cells remain controversial. We established a critical role Fig. 2. Schematic representation of biological of CAR in growth regulation of oral squamous cell effect of CAR (Coksackie and Adenovirus carcinomas (SCCs) in vitro and in vivo via specific interaction with Rho-associated protein kinase Receptor) on Rho A-associated kinase. Moderate suppression of ROCK activity by (ROCK). In particular, loss of endogenous CAR CAR facilitates growth, invasion and expression by knockdown using specific siRNA metastasis of SCC cells. facilitates growth suppression of SCC cells due to This work was published in “Oncogene” March cell dissociation, followed by apoptosis. The 18, 2013 [Epub ahead of print].

3. Anti-tumor impact of p14ARF on gefitinib-resistant non-small cell lung cancers Saito, K., Takigawa, N.,*1 Ohtani, N.,*2 Iioka, H., Tomita, Y., Ueda, R.,*3 Fukuoka, J., Kuwahara, K., Ichihara, E.,*4 Kiura, K.*4, and Kondo, E. Activation of the epidermal growth factor receptor (EGFR) has been observed in many malignant tumors and its constitutive signal transduction facilitates cell proliferation. EGFR-tyrosine kinase inhibitors, such as gefitinib, are widely used as molecular-targeting agents for Figure 3. Specific gene regulation downstream of inactivation of EGFR signaling and have shown activated EGFR in lung adenocarcinomas in considerable therapeutic effects in non-small cell response to gefitinib. p14ARF, a tumor lung cancers harboring activating EGFR mutations. suppressor gene, is recruited on treatment with gefitinib to EGFR-activated lung cancer cells, with However, prolonged treatment inevitably produces induction abrogated in gefitinib-resistant lung tumors with additional gefitinib-resistant mutations cancers derived from the sensitive parent cancer in EGFR, which is a critical issue for current cells. The p1438-65 peptide has potential as an therapeutics. In this study, we aimed to characterize antitumor tool for gefitinib-resistant lung cancers. distinct molecular responses to gefitinib between This report was highlighted in Molecular Cancer drug-resistant and drug-sensitive lung Therapeutics, an AACR journal. (Mol. Cancer adenocarcinoma cells. From quantitative PCR Ther. 12:1616-1628, 2013) analysis, we found a specific increase in p14ARF expression in gefitinib-sensitive lung 4. Lapatinib sensitivities of two novel adenocarcinoma clones, which was absent in trastuzumab-resistant HER2 gene- gefitinib-resistant clones. Moreover, ARF amplified gastric cancer cell lines mitochondria-targeted p14 triggered the most Oshima, Y.*1, Tanaka, H., Murakami, H.*1, Ito, Y.*2, apoptosis in both clones. We further identified the Furuya, T., Kondo, E., Kodera, Y.*1, and Nakanishi H. amino acid residues spanning from 38 to 65 as a ARF Trastuzumab (Tmab) resistance is a major functional core of mitochondrial p14 (p14 38-65 clinical problem needing resolution in patients with a.a.), which reduced the mitochondrial membrane HER2-positive gastric cancers. However, in potential and caused caspase-9 activation. The contrast to the situation for HER2-positive breast synthesized peptide covering the p14 38-65 a.a. cancer lines, Tmab-resistant gastric cancer induced growth suppression of gefitinib-resistant preclinical models that are needed to develop novel clones without affecting non-neoplastic cells. therapies to overcome this problem have not been Notably, transduction of a minimized dose of the available. We developed three new cell lines from “p14 38-65 peptide” restored the response to HER2 gene-amplified gastric cancer cell lines gefitinib to that in the sensitive clones. These ARF (GLM-1, GLM-4, NCI N-87) by a new in vivo findings suggest that the region of p14 38-65 a.a. selection method consisting of repeated culture of is critical in the pharmacological action of gefitinib small residual peritoneal metastases but not against EGFR-mutated lung adenocarcinoma cells subcutaneous tumors after Tmab treatment. We and has potential utility in the therapeutics of then evaluated the anti-tumor efficacy of lapatinib gefitinib-resistant cancers. in these Tmab-resistant cells. We successfully

*1 isolated two Tmab-resistant cell lines Department of General Internal Medicine 4, Kawasaki (GLM1-HerR2, GLM4-HerR2) among the three Medical School tested cell lines. The resistant cells differed from *2 Division of Cancer Biology, The Cancer Institute of their parents in their flat morphology and rapid the Japanese Foundation for Cancer Research (JFCR) *3 Department of Tumor Immunology, Aichi Medical growth in vitro, whereas HER2, P95HER2 University School of Medicine expression and Tmab binding were essentially the *4 Department of Respiratory Medicine, Okayama same in both parental and resistant cells. MUC4 University Hospital expression was up- or down-regulated depending on the cell line. The resistant cells were still sensitive to lapatinib, similar to the parental cells, in vitro. The growth inhibition of the Tmab-resistant cells by lapatinib was due to both G1 cell-cycle

4 arrest and apoptosis induction via effective * Institute of Neuropathology, Univ. Hosp. Giessen und blockade of the PI3K/Akt and MAPK pathways. A Marburg GmbH 5 preclinical study confirmed that the Tmab-resistant * Neurological Institute, Frankfurt University Medical tumors are significantly susceptible to lapatinib. School These results suggest that lapatinib has antitumor activity against Tmab-resistant gastric cancer cell lines, these latter being useful for understanding the mechanism of Tmab resistance and for developing new molecular therapeutic approaches.

1 * Dep. of Gastroenterological Surgery, Nagoya University Graduate School of Medicine 2 * Dep. of Gastroenterological Surgery, Aichi Cancer Center Central Hospital

5. LGR5 is a marker of poor prognosis in glioblastoma and is required for survival of brain cancer stem-like cells Nakata, S., Campos, B.*1, Bageritz, J.*2, Bermejo, JL.*3, Becker, N.*2, Engel, F.*2, Acker, T.*4, Momma, S.*5, Herold-Mende, C.*1, Lichter, P.*2, Radlwimmer, B.*2, and Goidts, V.*2 With various types of cancers including glioblastoma, there is accumulating evidence of the existence of cancer stem-like cells (CSCs), characterized by stem cell marker expression, capacity for differentiation and self-renewal, and a high potential for tumor propagation in vivo. LGR5, whose expression is positively regulated by the Wnt signaling pathway, is a stem cell marker in various adult tissues, including intestinal mucosa and hair follicles in the skin. As Wnt signaling is also involved in brain development, we investigated the function of LGR5 in the maintenance of brain CSCs. Our study showed that the LGR5 transcript level was increased in brain CSCs in vitro, and in CD133-positive glioblastoma cells in tumor tissues. Functionally, silencing of LGR5 by lentiviral shRNA-mediated knockdown induced apoptosis in brain CSCs. Moreover, LGR5 depletion led to a downregulation of L1 cell adhesion molecule expression, which has been shown to be indispensible for brain CSCs. In line with an important function in glioma tumorigenesis, LGR5 expression could be shown to be increased with glioma progression and correlated with an adverse outcome. Our findings suggest that LGR5 plays a role in maintenance and/or survival of brain CSCs.

1 * Div. of Neurosurgical Research, Dep. of Neurosurgery, University of Heidelberg 2 * Div. of Molecular Genetics, German Cancer Research Center, Heidelberg 3 * Institute of Medical Biometry and Informatics, University Hospital Heidelberg

From left to right First row: Dr. Ichidai Tanaka, Dr. Hiromi Furuta, Dr. Yoshitaka Sekido, Ms. Mari Kizuki, Dr. Makiko Fujii, Dr. Yuko Murakami-Tonami.. Second row: Dr. Asuki Fukatsu, Mr. Yoshio Tatematsu, Dr. Akihiro Matsushita, Dr. Hirotaka Osada, Ms. Yumi Nakahama, Mr. Ryuma Takao, Ms. Miwako Nishizawa, Dr. Shuhei Hakiri.

______Division of Molecular Oncology ______

Yoshitaka Sekido M.D., Ph.D., Chief Hirotaka Osada, M.D., Ph.D., Section Head Yutaka Kondo, M.D., Ph.D., Section Head (until October 2012) Makiko Fujii, D.D.S., PhD., Senior Researcher Yuko Murakami-Tonami, M.D., Ph.D., Senior Researcher (as of September 2012) Yoshio Tatematsu, B.S., Research Assistant Yasue Matsudaira, B.S., Research Assistant (until March 2012) Miwako Nishizawa, B.P., Research Assistant (as of April 2012) Mari Kizuki, Semi-regular Employee (as of July 2012) Yumi Nakahama, Semi-regular Employee (as of March 2013)

Research Resident Futoshi Ishiguro, M.D., Nagoya University Graduate School of Medicine (until March 2012) Yukiko Atsuta, M.D., Nagoya University Graduate School of Medicine (April ~ June 2012) Ichidai Tanaka, M.D., Nagoya University Graduate School of Medicine (July ~ December 2012), Research Resident of the Foundation for Promotion of Cancer Research (as of January 2013) Asuki Fukatsu, M.D., Nagoya University Graduate School of Medicine (as of April 2013) Fumiharu Ohka, M.D., Nagoya University Graduate School of Medicine (until October 2012) Keisuke Katsushima, M.S., Hokkaido University Graduate School of Life Science (April ~ October 2012)

Visiting Trainees Keiko Shinjo, M.D., Nagoya University Graduate School of Medicine (until May 2012) Keisuke Katsushima, M.S., Hokkaido University Graduate School of Life Science (until March, 2012) Ichidai Tanaka, M.D., Nagoya University Graduate School of Medicine (April ~ June 2012) Asuki Fukatsu, M.D., Nagoya University Graduate School of Medicine (until March 2013) Shuhei Hakiri, M.D., Nagoya University Graduate School of Medicine (as of April 2013) Hiromi Furuta, M.D., Nagoya City University Graduate School of Medicine (as of April 2013) Akihiro Matsushita, M.D., Nagoya University Graduate School of Medicine (as of November 2013) Ryuma Takao, Meijo University (February ~ December 2013) Shiho Inagaki, Kinjo University (August ~November 2013)

General Summary Our goal is to determine genetic lesions and epigenetic alterations giving rise to human solid cancers and use this information for prevention, diagnosis, and treatment of disease. The research also provides opportunities to dissect biochemical and pathological pathways of malignant phenotypes including deregulated cell proliferation, invasion, metastasis and drug resistance. Currently, we are especially focusing on malignant mesothelioma and lung cancer. Human cancers arise because of genetic mutations in oncogenes and tumor suppressor genes, and we are approaching this by study of candidate genes, systematic molecular analysis of biochemical pathways, and global approaches such as microarray analysis of gene expression profiling, comparative genomic hybridization techniques for chromosomal abnormalities, and next generation sequencing. Epigenetic changes with DNA methylation, histone modification, and microRNA expression also indicate these to be not only involved in inactivation of tumor suppressor genes but also to contribute to fundamental mechanisms of regulation of maintenance of cancer stem cell populations and differentiated cell lineages . We also functionally analyze candidate genes by transducing wild type copies into human cancer cells and testing for their ability to suppress malignancy in vitro and in vivo as well as characterizing their protein products biochemically. Alternatively, we inactivate expression using RNA interference (RNAi) in either tumor or normal cells and then study resultant phenotypes. Understanding the functions of mutated genes and disrupted signaling pathways will hopefully provide a foundation for translational research for human malignancies from bench to bedside.

1. LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via the Hippo signaling cascade Tanaka, I., Osada, H., Fujii, M., Fukatsu, A., Hida, T.*1, Horio, Y. *1, Kondo, Y. *2, Sato, A.*3, Hasegawa, Y. *4, Tsujimura, T.*3, and Y Sekido Malignant mesothelioma (MM) is one of the most aggressive neoplasms usually associated with asbestos exposure and is highly refractory to current therapeutic modalities. MMs show frequent activation of a transcriptional coactivator Yes-associated protein (YAP), which is attributed to neurofibromatosis type 2 (NF2)–Hippo pathway dysfunction, leading to deregulated cell proliferation and acquisition of a malignant phenotype. However, the detailed mechanisms of disordered YAP activation in MMs have yet to be Fig. 1 (A) Western blotting analysis of AJUBA, well clarified. We investigated various components YAP and phospho-YAP Ser127 (p-YAP). AJUBA of the NF2-Hippo pathway, and eventually found expression was undetectable in 15 and that MM cells frequently show downregulation of significantly low in 3 of 24 MM cell lines LIM-domain protein AJUBA, a binding partner of compared to an immortalized normal large tumor suppressor 2 (LATS2), one of the mesothelial cell line, MeT-5A. YAP last-step kinases in the NF2-Hippo pathway. phosphorylation was remarkably reduced in 21 Although loss of AJUBA expression proved of 24 MM cell lines compared to MeT-5A. independent of the alteration status of other Hippo Expression of β-actin used as a control. (B) pathway components, MM cell lines with AJUBA Cell proliferation assays. After infection with inactivation showed a more dephosphorylated AJUBA-expressing or empty lentiviruses, (activated) level of YAP. Immunohistochemical calorimetric assays were performed at each analysis showed frequent downregulation of time point. AJUBA transduction significantly AJUBA in primary MMs, which was associated inhibited the cell proliferation of NCI-H290 and with YAP constitutive activation. We further found Y-MESO-8D cells. (C) Soft agar colony that AJUBA transduction into MM cells formation assays with AJUBA transduction. significantly suppressed promoter activity of After 12-days incubation, colonies were stained YAP-target genes, and the suppression of YAP with 0.03% crystal violet. activity by AJUBA was remarkably canceled by Anchorage-independent growth was knockdown of LATS2. In connection with these significantly suppressed in NCI-H290 and Y-MESO-8D cell lines. results, transduction of AJUBA-expressing lentivirus significantly inhibited the proliferation and anchorage-independent growth of MM cells featuring normal LATS family expression. Taken 2. RASSF3 downregulation increases together, our findings indicate that AJUBA malignant phenotypes of non-small cell negatively regulates YAP activity through the LATS lung cancer family, and inactivation of AJUBA is a novel key Fukatsu, A., Ishiguro, F. *1, Tanaka, I., Kudo, T*2, *3, mechanism in MM cell proliferation. Nakagawa, K.*2, Shinjo, K.*4, Kondo, Y. *5, Fujii, M., Hasegawa, Y. *6, Tomizawa, K.*7, Mitsudomi, T.*7, *8, *1Department of Thoracic Oncology, Aichi Cancer Center, Osada, H., Hata, Y. *2, and Sekido, Y. Nagoya, Japan Ras-Association Family1A (RASSF1A) is a *2 Division of Epigenomics, Aichi Cancer Center well-established tumor suppressor. Ten RASSF Research Institute, Nagoya, Japan *3 homologues comprise the family, and each member Department of Pathology, Hyogo College of Medicine, is considered a tumor suppressor. RASSF3 is one Nishinomiya, Japan for which functions have yet to be clarified in detail. *4Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan; Recently, we found that RASSF3 interacts with MDM2 and facilitates its ubiquitination, which induces apoptosis through p53 stabilization.

However, the role of RASSF3 in human malignancies remains largely unknown. Ninety-five non-small cell lung cancer (NSCLC) patients from Nagoya University Hospital and 45 NSCLC patients from Aichi Cancer Center Hospital underwent pulmonary resection at each hospital, and lung cancer and corresponding non-cancerous lung tissues were collected. The expression levels of RASSF3 were analyzed using quantitative real-time reverse transcription PCR. We performed statistical analysis to investigate the correlation Fig. 2. (A) Relative expression levels of the with RASSF3 expression and clinicopathological RASSF3 gene of NSCLC tumor samples from characteristics. We also transfected RASSF3-siRNA Nagoya University hospital and corresponding into NSCLC cells, and performed motility assays to non-cancerous lung tissues. The mean RASSF3 evaluate the influence on migration ability. expression level of the non-tumor samples was RASSF3 expression levels were down-regulated in arbitrarily set as 1.0. Expression levels of tumor (blue line) and lung tissue (red line) are indicated 125 of the total of 140 NSCLCs. On multivariate side by side from the same patients, with the logistic regression analysis, low RASSF3 lowest RASSF3 level of the tumor starting from the expression below the median value was left. Note the frequent down-regulation in NSCLCs. independently correlated with progressive (B) Wound healing assay of RASSF3-knockdown phenotypes (lymph node metastasis and pleural cells. Forty-eight hours after transfection, A549 invasion), non-adenocarcinoma histology and cells were re-plated in 3.5 cm dishes. After the cells wild-type epidermal growth factor receptor (EGFR) had grown to confluence, cultures were damaged status. In motility assays, RASSF3-knockdown using a 1-200 μl beveled orifice tip and then NSCLC cells increased the migration rate compared allowed to migrate. Photographs were taken at the to control cells. Together, our findings indicate indicated time points. RASSF3-knockdown cells RASSF3 is a candidate tumor suppressor gene for demonstrated increased migration rates as NSCLCs. compared to the control. siCont; siRNA of negative control, siRF3; siRNA against RASSF3. *1Departments of General Thoracic Surgery, Graduate School of Medicine, Nagoya University, Nagoya, Japan *2Departments of Medical Biochemistry, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan *3Departments of Neurosurgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan *4Departments of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan *5Division of Epigenomics, Aichi Cancer Center Research Institute, Nagoya, Japan *6Departments of Respiratory Medicine, Graduate School of Medicine, Nagoya University, Nagoya, Japan *7Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan *8Department of Thoracic Surgery, Kinki University Faculty of Medicine, Sayama, Japan

From left to right First row: Dr. S. Tsuzuki, Dr. M. Seto, Ms. K. Hirano, Ms. Y. Kasugai Second row: Ms. S. Sato, Dr. N. Yoshida, Dr. T. Takahara, Dr. M. Katayama, Dr. T. Kakiuchi

______Division of Molecular Medicine ______

Masao Seto, M.D., Ph.D. Chief Shinobu Tsuzuki, M.D., Ph.D. Section Head Kennosuke Karube, M.D., Ph.D. Senior Researcher (until December 2012) Miyuki Katayama, M.D., Ph.D. Senior Researcher Yumiko Kasugai, B.S. Research Assistant Kotaro Arita, M.D. Research Resident (until October 2013) Taishi Takahara, M.D. Research Resident Kyoko Hirano, B.S. Research Assistant

Visiting Trainees Noriaki Yoshida, M.D. Nagoya University Graduate Shool of Medicine Tatsuo Kakiuchi, M.D. Nagoya University Graduate Shool of Medicine

General Summary Research in this laboratory is focused on elucidating genetic and molecular bases of human cancer, with a view to applying the obtained knowledge for clinical oncology. We are working on hematological malignancies, in collaboration with physicians in the Department of Hematology and Cell Therapy (Chief, Dr. Tomohiro Kinoshita) of Aichi Cancer Center Central Hospital. The group of diseases is highly associated with genetic changes so that some malignancies can be classified according to genetic changes specific to given entities. Such close association provides evidence that the genetic changes play pivotal roles in disease development and/or clinicopathological manifestations. Over the last two years, we have studied several issues in particular: (1) possible involvement of deregulated cell cycling, in particular that associated with loss of CDKN2A, in the transformation of chronic type adult T-cell leukemia/lymphoma and in its clinical outcome; (2) establishment of a method to generate lymphomas in mice employing in vitro-induced germinal center B and T cells; (3) identification of effective drugs against NK cell lymphoma; (4) involvement of clonal heterogeneity in the development of lymphoma and its impact on clinical outcome; (5) modeling first-hit functions of the TEL-AML1 fusion gene in establishment of a pre-leukemic state.

1. Cell cycle deregulation contributes to pathogeneses, and especially the molecular acute transformation in chronic type mechanisms of acute transformation. The use of adult T-cell leukemia/lymphoma aCGH revealed that genomic loss of 9p21.3 was 1 Yoshida, N., Karube, K., Utsunomiya, A.* , Tsukasaki, significantly characteristic of acute type ATL, but 2 2 3 4 K.* , Imaizumi, Y.* , Taira, N.* , Uike, N.* , Umino, A., not of chronic type ATL. Among the genes located 5 in the loss region, only CDKN2A expression was Arita, K., Katayama, M., Tsuzuki, S., Kinoshita, T.* , *6 reduced in accordance with genomic loss. Ohshima, K. , and Seto, M. Re-expression of CDKN2A (and especially of Adult T-cell leukemia/lymphoma (ATL) is a INK4a) suppressed proliferation of ATL cell lines. human T-cell leukemia virus type-1 induced Clinically, chronic type ATL patients with neoplasm with four clinical subtypes: acute, alterations in cell cycle-related genes including lymphoma, chronic, and smoldering. Although CDKN2A showed a poorer prognosis than patients chronic and smoldering subtypes are regarded as without such alterations. Additionally, the results of indolent, about half of these cases progress to acute GEP indicated that the pathophysiology of chronic type ATL and subsequent death. Therefore, acute type ATL samples with such alterations is close to transformation is a predictive indicator for patients that of acute type ATL. These findings suggested with indolent ATL. However, the underlying that cell cycle-related genes play an important role molecular mechanisms have not fully elucidated. In in acute transformation and should serve as good the present study, oligo-array comparative genomic new prognostic markers for chronic type ATL. hybridization (aCGH) and comprehensive gene-expression profiling (GEP) were applied to 27 *1 Department of Hematology, Imamura Bun-in Hospital, and 35 cases of chronic and acute type ATL, Kagoshima, Japan respectively, in an effort to determine molecular *2 Department of Hematology, Atomic Bomb Disease

21 and Hibakusha Medicine Unit, Atomic Bomb Disease study, we analyzed gene expression profiles of NK Institute, Nagasaki University, Nagasaki, Japan 3 cell neoplasms and attempted to identify important * Department of Internal Medicine, Heartlife Hospital, molecular pathways and new effective drugs. Okinawa, Japan 4 Pathway analysis of gene expression profiles * Department of Hematology, National Hospital suggested important roles of the JAK-STAT, NF-κB Organization Kyushu Cancer Center, Fukuoka, Japan *5 Department of Hematology and Cell Therapy, Aichi or Wnt pathways. Notably, Western blot analysis Cancer Center, Nagoya, Japan revealed that STAT3 was expressed and *6 Department of Pathology, School of Medicine, phosphorylated at a higher level in NK cell lines Kurume University,Kurume, Japan than in normal NK cells or other cell lines, indicating the occurrence of JAK-STAT activation 2. Generation of mouse models of in NK cell neoplasms. Connectivity Map (CMAP) lymphoid neoplasms using retroviral analysis of gene expression profiles identified gene transduction of in vitro-induced candidate drugs against NK cell neoplasms. Among germinal center B and T cells the suggested drugs , we focused on puromycin, 1 Arita, K., Maeda-Kasugai, Y., Ohshima, K.* , Tsuzuki, S., phenoxybenzamine, LY294002, wortmannin, 2 Katayama, M., Karube, K., Yoshida, N., Sugiyama, T.* , vorinostat and trichostatin A because they exhibited Seto, M. high enrichment scores. When added to NK cell Evidence is accumulating that hematologic lines and other cell lines, among the drugs, malignancies develop following acquisition of vorinostat suppressed NK cell line proliferation at a multiple genetic changes. Despite providing many significantly lower concentration. Suppression of insights into the way by which given genetic the JAK-STAT pathway appeared to contribute to changes contribute to the development of disease, this effect. Vorinostat may be a good candidate for the generation of animal models is often laborious. use in therapy against NK cell neoplasms.

We have focused on a simplified method that allows 1 the retroviral transduction of genes of interest into * Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital mouse B or T cells, thus leading to rapid generation 2 * Department of Pathology, Samsung Medical of models of lymphoid neoplasms in mice. Sungkyunkwan University School of Medicine, Republic Specifically, germinal center B cells induced in of Korea vitro from naive mouse B cells and infected with *3 Department of Pathology, School of Medicine, retroviruses for Myc and Bcl2 rapidly developed Kurume University, Kurume, Japan into neoplasms of immunoglobulin-expressing *4 Department of Pathology and Clinical Laboratories, mature B cells in transplanted mice. Likewise, T Nagoya University Hospital, Nagoya, Japan cells induced in vitro from immature hematopoietic cells and infected with retroviruses for Myc, Bcl2, 4. Clonal heterogeneity of lymphoid and Ccnd1 rapidly developed CD4(+)CD8(-) and malignancies is related to poor CD4(+)CD8(+) T cell neoplasms after prognosis 1 2 transplantation. These findings support use of our Katayama, M., Tagawa, H.* , Nakagawa, M.* , Fukuhara, 3 4 5 simplified method as a versatile tool for lymphoma N.* , Sivasundaram, S.* , Takeuchi, I. * , Kasugai, Y., research. Arita, K., Yoshida, N., Kakiuchi, T., Karube, K., Tsuzuki. S, Nakamura, S.*6, Seto, M.

*1 Department of Pathology, School of Medicine, Clonal heterogeneity means several sub-clones Kurume University,Kurume, Japan with different genomic aberrations in any particular *2 Third Department of Internal Medicine, Graduate tumor sample. Most of the cases with clonal School of Medicine and Pharmaceutical Sciences, heterogeneity result from clonal evolution which University of Toyama, Toyama, Japan makes tumors more aggressive. Here we identified 332 lymphoma samples (31 MALT lymphomas, 24 3. Comprehensive gene expression Burkitt lymphomas, 29 mantle cell lymphomas, 79 profiles of NK cell neoplasms indicate follicular lymphomas, 118 diffuse large B-cell vorinostat as an effective drug lymphomas (DLBCLs) and 51 peripheral T-cell candidate lymphomas, not otherwise specified) with or Karube, K., Tsuzuki, S., Yoshida, N., Arita, K., Kato, without clonal heterogeneity using array CGH 1 2 3 H.* , Katayama, M., Ko, YH.* , Ohshima, K.* , analysis. The frequency of clonal heterogeneity for 4 1 Nakamura, S.* , Kinoshita, T.* , Seto, M. each lymphoma varied from 24% to 69%. NK cell neoplasms are lymphoid malignancies Genomic aberrations for samples with clonal with an aggressive clinical course. In the present heterogeneity in multiple lymphoma species

22 included loss/deletion of 9p21.3 (CDKN2A/2B transcriptional program. locus) and 17p13 (TP53, ATP1B2, SAT2, SHBG locus). DLBCLs and mantle cell lymphomas with clonal heterogeneity demonstrated a significantly poorer prognosis than samples without clonal heterogeneity (p = 0.005 and p = 0.008, respectively). These results that clonal heterogeneity involving common genomic aberrations is present in all lymphoma types and is related to a poor prognosis, indicating this common phenomenon to be important for tumor progression.

*1 Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan *2 Metabolism Branch, Center for Cancer Research, National Cancer Institute, USA *3 Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Japan *4 Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan *5 Department of Computer Science/Scientific and Engineering Simulation, Nagoya Institute of Technology, Nagoya, Japan *6 Department of Pathology and Clinical Laboratories, Nagoya University Hospital, Nagoya, Japan

5. TEL (ETV6)-AML1 (RUNX1) initiates self-renewing fetal pro-B cells in association with a transcriptional program shared with embryonic stem cells in mice Tsuzuki, S., and Seto, M. The initial steps involved in the pathogenesis of acute leukemia are poorly understood. TEL-AML1 fusion gene usually arises before birth, producing a persistent and covert preleukemic clone that may convert to precursor B cell leukemia following accumulation of secondary genetic ‘‘hits.’’ Here, we showed that TEL-AML1 can induce persistent self-renewing pro-B cells in mice. TEL-AML11 cells nevertheless differentiate terminally in the long term, providing a ‘‘window’’ period that may allow secondary genetic hits to accumulate and lead to leukemia. TEL-AML1-mediated self-renewal is associated with a transcriptional program shared with embryonic stem cells (ESCs), within which Mybl2, Tgif2, Pim2, and Hmgb3 are critical components, sufficient to establish self-renewing pro-B cells. We further showed that TEL-AML1 increases the number of leukemia-initiating cells that are generated in cooperation with additional genetic hits, thus providing an overall basis for the development of novel therapeutic and preventive measures targeting the TEL-AML1-associated

From left to right First row: Dr. R. Zhang, Dr. A. Demachi-Okamura, Dr. K. Kuzushima, Ms. K. Hiramatsu Second row: Ms M. Tatsumi, Dr. N. Ueda Ms. K. Shiraishi, Dr. E. Yamada, Ms. R. Terada, Mr. H. Maki Inset: Dr. Y. Akatsuka, Dr. Y Uemura, Ms. T. Tsuboi

______Division of Immunology ______

Kiyotaka Kuzushima, M.D. Chief Mitsugu Fujita, M.D. Section Head (until March 2012) Yasushi Uemura, D.D.S. Senior Researcher (until August 2013) Ayako Demachi-Okamura, Ph.D. Researcher Shinji Kondo, M.D. Research Resident (until March 2012) Rong Zhang, Ph.D. Research Resident Eri Yamada, M.D. Research Resident (as of April 2012) Miwako Nishizawa, B.P. Senior Research Assistant (until March 2012) Kaho Hiramatsu, Research Assistant (as of April 2012) Rie Terada (Miura), Semi-regular Employee Minako Tatsumi, Semi-regular Employee Keiko Shiraishi, Semi-regular Employee Tomiko Tsuboi, Semi-regular Employee

Visiting Researcher Yoshiki Akatsuka, M.D. Department of Hematology & Oncology, Fujita Health University Mitsugu Fujita, M.D. Department of Neurosurgery and Department of Microbiology, Kinki University (as of April 2012) Yasushi Uemura, D.D.S. Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center (as of September 2013)

Visiting Trainees Hiroyuki Maki, Department of Cellular Oncology, Nagoya University Graduate School of Medicine Eri Yamada, M.D. Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine (as of January 2012 until March 2012) Shinji Kondo, M.D. Department of Gynecologic Oncology, Aichi Cancer Center (as of April 2012) Norihiro Ueda, M.D. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine (as of October 2012)

General Summary The object of our research is to establish molecular and cellular bases for novel cancer therapy taking advantage of immune responses. The achievements during past two years are as follows. Firstly, we explored the association of oncogenic K-ras mutation (G12V) with presentation of a CTL epitope derived from puromycin-sensitive aminopeptidase (PSA). Most pancreatic cancers are reported to harbor the mutation and consequently activated autophagy. In addition, the epitope has been demonstrated to be processed and presented in an autophagy-dependent manner. After transfection of the mutated K-ras and HLA-A*24:02, non-malignant human epithelial cells presented the epitope accompanied by induction of autophagy. These data suggest that the constitutive autophagy evoked by K-ras mutation causes unique processing and presentation of the CTL epitope, providing basic information for immunotherapy. Secondly, we sought to generate highly specific monoclonal antibodies (mAbs) for a minor histocompatibility antigen (mHAg), HA-1H, by immunizing HLA- A*02:01-transgenic mice with tetramerized recombinant HLA-A*02:01 protein incorporating the HA-1H peptide and β2-microglobulin (HA-1H/HLA-A2). The phage display technique was applied to select clones reactive to HA-1H/HLA-A2. Details are described in the text below. Thirdly, we established a system to facilitate proliferation of embryonic stem (ES) or induced pluripotent stem (iPS) cell-derived myeloid cells. The cells exhibit cytokine-dependent proliferation and dendritic cell (DC)-like differentiation and thus may offer a solution to current problems in preparing sufficient numbers of DCs. Lastly, we investigated the role of human invariant natural killer (iNK) T cells in regulation of IL-12p70 and osteopontine (OPN) production by DCs. We found that iNKT cells modify the IL-12p70/OPN balance to

25 enhance IL-12p70-induced cell-mediated immunity and suppress the OPN-dependent inflammatory condition that promotes tumor development. An aspect of the protective role of iNKT cells in tumor immunosurveillance seems to be elucidated by these findings.

1. Constitutively active autophagy causes minor histocompatibility antigen HA-1H *1,2 *1 *3 a CTL epitope generation in pancreatic Akatsuka, Y. , Inaguma, Y. , Aka ho r i, Y. , Murayama, Y. *1, Shiraishi, K., Endoh, A.*1, Demachi-Okamura, A., cancer cells *4 *5 Demachi-Okamura, A., Kuzushima, K. Hiramatsu, K., Nishimura, Y. , Takahashi, To. , Emi, *1 Tumor antigen-specific cytotoxic T N. , and Kuzushima, K. lymphocytes (CTLs) play a crucial role in immune Selective graft-versus-tumor (GVT) reactivity system-mediated elimination of cancer. They exert with minimal risk of graft-versus-host disease such effects through recognition of tumor (GVHD) following allogeneic stem cell antigen-derived peptides bound to human leukocyte transplantation is thought to be induced by targeting antigens (HLAs) on cell surfaces. Antigen minor histocompatibility (H) antigens (Ags) processing pathways to produce the peptides in expressed only on patients’ hematopoietic cells. particular cancer cells remain to be fully elucidated. Among HLA-A*02:01 positive patients, minor H To study one such pathway, we used a CTL clone Ags such as HA-1 have been shown to be designated 16F3 which recognizes associated with anti-tumor responses with minimal puromycin-sensitive aminopeptidase (PSA) in an GVHD and thus have been explored for HLA-A*24:02-restricted manner. Generation of the applications in adoptive immunotherapy. Because epitope recognized by 16F3 requires proteasomal preparation of Ag-specific cytotoxic T cell clones degradation and transportation from the (CTLs) or lines for adoptive immunotherapy is endoplasmic reticulum to the Golgi apparatus as labor-intensive, genetic transfer of T-cell receptors demonstrated in drug inhibition assays. (TCRs) directed toward target Ags into T Autophagy is also required in the epitope lymphocytes has been employed to efficiently processing as evidenced by RNAi-mediated generate anti-tumor T cells. Alternatively, T cells autophagy-mediated gene silencing. could be gene-modified with a chimeric antigen Immunofluorescence revealed high levels of receptor (CAR) harnessing a single chain antibody autophagic activity in pancreatic cancer cells that moiety (scFv). The conventional CAR strategy has are sensitive to CTL-mediated lysis. As previously the limitation of only targeting cell surface Ags on reported, constitutively activated autophagy is target cells. One possible way to attain intracellular associated with oncogenic K-ras mutation (G12V) Ag targeting with a CAR is to generate a TCR-like in such pancreatic cancer cells. Thus we sought to monoclonal antibody (mAb) as a source of scFv. study whether K-ras mutation mightresult in PSA We sought to generate highly specific mAbs epitope generation through activation of autophagy. specific for HA-1H minor H Ag by immunizing To this end, MCF10A, a non-tumorigenic mice with tetramerized recombinant HLA-A2 human breast epithelial cell line, was transfected incorporating HA-1H minor H Ag peptides and with mutated K-ras. Many autophagosomes β2-microglobulin (HA-1H/HLA-A2). We emerged in MCF10A cells after the transfection. hypothesized that the use of HLA-A2 transgenic Additional transfection of HLA-A*24:02 enabled mice, which should be tolerant to human HLA-A2, the cells to stimulate 16F3 for IFN-γ production. would facilitate efficient induction of mAbs specific Interestingly, induction of autophagy using for peptides presented on HLA-A2. Phage libraries chemicals or nutritional deprivation did not result in were generated from splenic B cells and screened the same epitope liberation as observed with K-ras by panning for clones reactive to plate-bound mutation. These data suggest that the constitutively HA-1H/HLA-A2 in the presence of irrelevant free active autophagy evoked by K-ras mutation causes MAGEA4/HLA-A2 for competition. Candidate unique processing and presentation of the CTL scFv encoded by obtained phage clones was epitope in a part of pancreatic cancer cells and transformed to an scFv tetrameric Ab form or provide important information for cancer introduced into T cells as CAR coupled to CD28 immunotherapy. transmembrane and CD3ζ domains (CD28-ζ). A total of 144 clones were randomly selected from 8.1×108 clones that had been recovered after the 2. Construction and molecular character- third panning. Among these, 18 (12.5%) showed ization of a T-cell receptor-like preferential binding to HA-1/HLA-A2, 137 showed antibody and CAR-T cells specific for similar binding to both pMHC complexes, and 7

26 showed reactivity to neither of them. One of 18 tumor-associated antigen (TAA)-specific T cell scFv Abs, clone #131, demonstrated high affinity responses. With U.S. Food and Drug Administration (KD = 14.9nM) for the HA-1H/HLA-A2 complex. approval of the first DC-based vaccine, Provenge, Primary human T cells transduced with #131 an autologous DC-based therapy is being scFv-CD28-ζ were stained with HA-1H/HLA-A2 established as a new cell modality for cancer tetramers as strongly as a cognate CTL clone, EH6, treatment. However, the preparation of autologous specific for endogenously HLA-A2- and DC therapeutics is expensive for patients and HA-1H-positive cells. Unexpectedly, however, technically demanding for clinicians, not to mention #131 scFv-CD28-ζ CAR-T cells required an the difficulty involved with large-scale industrial ~100-fold higher Ag density when pulsed production. exogenously to exert cytotoxicity than did the Pluripotent stem cells such as embryonic stem cognate EH6-CTL. In addition, mAb blocking (ES) cells and the recently developed induced experiments demonstrated that #131 scFv-CD28-ζ pluripotent stem (iPS) cells have the potential to CD8+ CAR-T cells were less sensitive to CD8 propagate indefinitely and possess the ability to blockade when they were completely blocked with differentiate into various types of somatic cells. HA-1H/HLA-A2 tetramers, and even #131 Several groups, including ours, have thus far scFv-CD28-ζ CD4+ CAR-T cells lysed the target in established methods to generate DCs from a similar way to #131 scFv-CD28-ζ CD8+ CAR-T pluripotent stem cells and demonstrated utility of cells. These data suggest that T cells with higher pluripotent stem cell-derived DC in cancer affinity antigen receptors than TCRs (average KD immunotherapy. However, the methods are too ranging between 1μM~100μM) are less able to laborious for practical application in the clinic. In recognize low density peptide/MHC antigens, as addition, generating DCs from pluripotent stem reported in the case of affinity-matured TCR or cells takes more than one month. CAR, and that CD8+ CAR-T cells may not be For the purpose of overcoming these obstacles, necessarily CD8-dependent possibly due to failure we established a system to induce proliferation of to form complexes with CD3. Because #131 the ES or iPS cell-derived myeloid cells by scFv-CD28-ζ CD8+ CAR-T cells could mount lentivirus-mediated transduction of the cMYC gene. IFN-γ, TNF-α and IL-2 production when stimulated Proliferating myeloid cells (pMCs) have the ability by K562/HLA-A2 cells transduced with HA-1H to propagate for more than three months in a minigene, a different level of signaling threshold GM-CSF-dependent manner while retaining the might exist between cytotoxic function and potential to differentiate into DC-like cells. In cytokine production. CAR-T cells with scFv with maintenance culture medium containing both lower KD are currently being tested to examine the GM-CSF and M-CSF, the pMCs expressed underlying mechanisms. DEC205, CD11b, CD11c, CD80, CD86, and Gr-1, but neither MHC-I nor MHC-II. Two days after *1 Department of Hematology, School of Medicine, Fujita removal of M-CSF, the pMCs differentiated into Health University. immature DC-like cells (pMC-DCs), as indicated *2 Visiting Researcher, Division of Immunology *3 by the expression of MHC-I and low levels of Division of Antibody Project, Institute for CD40, CD86, and MHC-II. Comparable to Comprehensive Medical Science, Fujita Health BM-derived immature DCs, they stimulated a University. *4 Department of Immunogenetics, Graduate School of primary mixed lymphocyte reaction (MLR). In Medical Sciences, Kumamoto University. addition, LPS exposure induced production of *5 Aichi Comprehensive Health Science Center, Aichi TNF-α and IL-12p70 and significantly enhanced Health Promotion Foundation. the expression of MHC-II and CD86, suggesting a typical DC maturation. Furthermore, the in vivo transfer of pMC-DCs pulsed with H-2Kb-restricted 3. Pluripotent stem cell-derived prolifera- OVA 257-264 peptide primed OVA-specific cytotoxic ting myeloid cells as a possible basis T cells and elicited protection against challenge for cellular vaccine cancer immuno- wit h OVA-expressing melanoma. therapy *1 Myeloid cells exhibiting cytokine-dependent Zhang, R., Liu, T. , Maki, H., Kuzushima, K., and Ue mura, Y. proliferation and DC-like differentiation may offer Dendritic cells (DCs) are one of the attractive a feasible cellular vaccine approach for cancer targets in efforts to generate therapeutic immunity immunotherapy. This would offer a solution to the against cancer, because of their ability to initiate problems currently faced in preparing sufficient numbers of DCs. 27

Beijing, China. *1 Cancer Center, Chinese PLA General Hospital., Beijing, China.

4. Modification of IL-12p70/osteopontin balance in dendritic cells by ligand activation of invariant NKT cells Zhang, R., Liu, T.*1, Kuzushima, K., and Uemura, Y. Invariant NKT cells constitute a unique subset of T lymphocytes characterized by expression of a semi-invariant TCR composed of a canonical invariant TCR α-chain (Vα14-Jα18 for mice and Vα24-Jα18 for humans) and a TCR β-chain using limited Vβ segments (Vβ8.2, Vβ7, Vβ2 in mice and a Vβ11 in humans). The biased TCR usage appears to confer on iNKT cells the capacity to recognize a limited number of glycolipid antigens presented by CD1d. α-Galactosylceramide (α-GalCer), a synthetic glycosphingolipid originally derived from a marine sponge, activates iNKT cells to rapidly produce large amounts of both Th1 and Th2 cytokines, which, in turn, license dendritic cell (DC) functions, promoting protective antitumor immunity. However, the nature of the protective role of invariant NKT (iNKT) cells in the tumor immunosurveillance remains to be fully elucidated. IL-12p70, a heterodimeric cytokine comprised of a p35 subunit and a p40 subunit, plays a crucial role in the cell-mediated immune response. Contrasting with the function of IL-12p70, osteopontine (OPN) is a potent proinflammatory cytokine that can be expressed by both tumor cells and cellular components of the tumor microenvironment. Elevated levels of OPN in tumor tissue and blood circulation are associated with tumor metastasis and a poor prognosis. We investigated the role of human iNKT cells in the regulation of IL-12p70 and OPN production by DCs. Activation of iNKT cells by their specific ligand α-GalCer enhanced IL-12p70 while inhibiting the OPN production. The differential regulation of IL-12p70/OPN appears mainly mediated by their harmonious Th1/2 cytokine production. In particular, the down regulation of OPN was found to be associated with a production of IL-4, IL-13, and IFN-γ from iNKT cells. In contrast, these cytokines synergistically enhanced IL-12p70 production. These findings indicate that iNKT cells modify the IL-12p70/OPN balance to enhance IL-12p70-induced cell-mediated immunity and suppress the OPN-dependent inflammatory condition that promotes tumor development.

*1 Cancer Center, Chinese PLA General Hospital.,

From left to right Dr. Teru Kanda, Dr. Daisuke Kawashima, Dr. Sho Nakasu, Ms. Ayako Watanabe, Mr. Yohei Narita, Dr. Tatsuya Tsurumi

______Division of Virology ______

Tatsuya Tsurumi, M.D., Ph.D. Chief Teru Kanda, M.D., Ph.D. Section Head Sho Nakasu, PhD. Senior Researcher Takayuki Murata, Vet. M.D., Ph.D. Researcher (until April 2013) Shinichi Saito, Ph.D. Research Resident (until August 2012) Daisuke Kawashima, Ph.D. Research Resident Chieko Noda, Research Assistant (until March 2012) Yohei Narita, Research Assistant (as of April 2012) Toshiko Gamano, Semi-regular employee (until May 2013)

Visiting Trainee Atsuko Sugimoto, Nagoya University Graduate School of Medicine Yohei Narita, Nagoya University Graduate School of Medicine Yoshitaka Sato, Kobe University School of Medicine

General Summary Approximately 15% of all human cancers have a viral etiology, but only six viruses have actually been unequivocally implicated in neoplastic development. Among these the Epstein-Barr virus (EBV) is the primary object of our own studies. EBV is a ubiquitous gamma herpesvirus associated with several malignant diseases, including Burkitt’s lymphoma, nasopharyngeal lymphoma, a subset of Hodgkin’s lymphomas, some gastric cancers, and B cell lymphomas in immunosuppressed patients. Our research aims are to elucidate the molecular mechanisms of viral proliferation and oncogenesis of EBV as part of the world-wide effort to combat virus-infected cancers. During the period 2012-2013, our research interest was concentrated on the following issues: 1) Interaction between basic residues of Epstein-Barr virus EBNA1 protein and cellular chromatin mediates viral plasmid maintenance; 2) Contributions of myocyte enhancer factor 2 (MEF2) family transcription factors to BZLF1 expression in Epstein-Barr virus reactivation from latency; 3) Repression by heat shock protein 90 inhibitors of latent membrane protein 1 (LMP1) expression and proliferation of Epstein-Barr virus-positive natural killer cell lymphoma cells; 4) Different distributions of Epstein-Barr virus early and late gene transcripts within viral replication compartments; 5) Nuclear transport of Epstein-Barr virus DNA polymerase dependence on the BMRF1 polymerase processivity factor and molecular chaperone Hsp90; 6) Epstein-Barr virus deubiquitinase downregulation of TRAF6-mediated NF-κB signaling during productive replication; 7) Pin1 interaction with the Epstein-Barr virus DNA polymerase catalytic subunit and regulation of viral DNA replication; 8) HLA-restricted presentation of WT1 tumor antigens in B-lymphoblastoid cell lines established using a maxi-EBV system; 9) Epigenetic histone modification of the Epstein-Barr virus BZLF1 promoter during latency and reactivation in Raji cells.

1. Interaction between Basic Residues of (chromatin) via its chromosome binding domains Epstein-Barr Virus EBNA1 Protein and (CBDs), which are rich in glycine and arginine Cellular Chromatin Mediates Viral residues. However, the molecular mechanisms by Plasmid Maintenance which the CBDs of EBNA1 attach to cellular Kanda, T. and Tsurumi, T. chromatin are still under debate. Mutation analyses The Epstein-Barr virus (EBV) genome is revealed that stepwise substitution of arginine episomally maintained in latently infected cells, the residues within the CBD1 (amino acids 40–54) and viral protein EBNA1 acting as a bridging molecule CBD2 (amino acids 328–377) regions with alanines that tethers EBV episomes to host mitotic progressively impaired chromosome binding of chromosomes as well as to interphase chromatin. EBNA1. Complete arginine-to-alanine substitutions EBNA1 localizes to cellular chromosomes within the CBD1 and -2 regions abolished the 30 ability of EBNA1 to stably maintain EBV-derived normally exhibits only low basal activity but is oriP plasmids in dividing cells. Importantly, activated in response to chemical or biological replacing the same arginines with lysines had inducers. Using a reporter assay system, we minimal effects, if any, on chromosome binding of screened for factors that can activate Zp and EBNA1 as well as on its ability to stably maintain isolated genes, including MEF2B, KLF4, and some oriP plasmids. Furthermore, a glycine-arginine-rich cellular b-zip family transcription factors. After peptide derived from the CBD1 region bound to confirming their importance and functional binding reconstituted nucleosome core particles in vitro, as sites in reporter assays, we then prepared did a glycine-lysine rich peptide, whereas a recombinant EBV-BAC in which the binding sites glycine-alanine rich peptide did not. These results were mutated. Interestingly, the MEF2 mutant virus support the idea that the chromosome binding of produced very low levels of BRLF1, another EBNA1 is mediated by electrostatic interactions transactivator of EBV, in addition to BZLF1 in between basic amino acids within the CBDs and HEK293. The virus failed to induce a subset of negatively charged cellular chromatin. early genes, such as BALF5, upon lytic induction, and accordingly, could not replicate to produce progeny viruses in HEK293 cells, but this restriction could completely be lifted by exogenous supply of BRLF1 together with BZLF1. In B cells, induction of BZLF1 by chemical inducers was inhibited by point mutations in the ZII or the three SP1/KLF binding sites of EBV-BAC Zp, while leaky BZLF1 expression was less affected. Mutation of MEF2 sites severely impaired both spontaneous and induced expression of not only BZLF1 but also BRLF1, in comparison to wild-type or revertant virus cases. We also observed MEF2 mutant EBV to feature relatively high repressive histone methylation, such as H3K27me3, but CpG DNA methylation levels were comparable around Zp and Rp. These findings shed light on BZLF1 expression and EBV reactivation from latency.

3. Heat shock protein 90 inhibitors repress latent membrane protein 1 (LMP1) expression and proliferation of Fig. 1. These live confocal microscopic images Epstein-Barr virus-positive natural depict an mCherry (red fluorescent protein) killer cell lymphoma cells fused to the chromosome binding domains of Murata, T. and Tsurumi, T. Epstein-Barr virus EBNA1 colocalizing with Epstein-Barr virus (EBV) LMP1, a major histone H2B-GFP-labeled chromatin in mitotic oncoprotein expressed in latent infection, functions HeLa cells. A merged image is at the bottom. as a TNFR family member and constitutively This imaging system was used to reveal that activates cellular signals, such as NFκB, MAPK, the basic nature of the chromosome binding domains of EBNA1 is primarily important for its JAK/STAT and AKT. We here screened small chromosome binding. molecule inhibitors and isolated HSP90 inhibitors, Radicicol and 17-AAG, as candidates that suppress

LMP1 expression and cell proliferation not only in 2. Contribution of Myocyte Enhancer EBV-positive SNK6 natural killer (NK) cell Factor 2 (MEF2) Family Transcription lymphoma cells, but also in B and T cells. Tumor Factors to BZLF1 Expression in formation in immuno-defficient Epstein-Barr virus Reactivation from NOD/Shi-scid/IL-2Rγnull (NOG) mice was also Latency retarded. These results suggest that HSP90 Murata, T. and Tsurumi, T. inhibitors can be alternative treatments for patients Reactivation of the Epstein-Barr virus (EBV) from with EBV-positive malignancies. latency is dependent on expression of the viral transactivator BZLF1 protein, whose promoter (Zp)

4. Different Distributions of Epstein-Barr 5. Nuclear Transport of Epstein-Barr Virus Early and Late Gene Transcripts Virus DNA Polymerase is Dependent within Viral Replication Compartments on the BMRF1 Polymerase Sugimoto, A., Sato, Y., Murata, T., Kanda, T., and Processivity Factor and Molecular Tsurumi, T. Chaperone Hsp90 Productive replication of the Epstein-Barr virus Kawashima, D., Murata, T., Kanda, T., and Tsurumi T. (EBV) occurs in discrete sites in nuclei, called Epstein-Barr virus (EBV) replication proteins are replication compartments, where viral genome transported into the nucleus to synthesize viral DNA synthesis and transcription take place. The genomes. We have focused on molecular replication compartments include subnuclear mechanisms for nuclear transport of EBV DNA domains, designated BMRF1 cores, which are polymerase. The EBV DNA polymerase catalytic highly enriched in the BMRF1 protein. During viral subunit BALF5 was found to accumulate in the lytic replication, newly synthesized viral DNA cytoplasm when expressed alone, while the EBV genomes are organized around and then stored DNA polymerase processivity factor BMRF1 inside BMRF1 cores. Here, we examined spatial moved into the nucleus by itself. Coexpression of distribution of viral early and late gene mRNAs both proteins, however, resulted in efficient nuclear within replication compartments using confocal transport of BALF5. Deletion of the nuclear laser scanning microscopy and three-dimensional localization signal of BMRF1 diminished the surface reconstruction imaging. EBV early mRNAs protein nuclear transport, although both proteins were mainly located outside the BMRF1 cores, could still interact. These results suggest that while viral late mRNAs were identified inside, BALF5 interacts with BMRF1 to effect transport corresponding well with the fact that late gene into the nucleus. Interestingly, we found that Hsp90 transcription is dependent on viral DNA replication. inhibitors or knockdown of Hsp90β with short From these results, we speculate that sites for viral hairpin RNA prevented the BALF5 nuclear early and late gene transcription are separated with transport, even in the presence of BMRF1, both in reference to BMRF1 cores. transfection assays and in the context of lytic replication. Immunoprecipitation analyses

Fig. 2. RNAPII becomes localized inside BMRF1 cores at late stages of productive replication. Tet-BZLF1/B95-8 cells were treated with doxycycline to induce lytic replication and harvested at the indicated post-induction times. After treatment with mCSK buffer, they were fixed. (A) Harvested cells were stained with anti-BMRF1 (green), anti-BALF2 (red), and anti-RNAPII (yellow) antibodies and observed by laser scanning confocal microscopy. The 2D images show brightest-point projections. Lower panels are merged images of the indicated combinations of the proteins. Pol II, RNA polymerase II. (B) Lytic replication-induced cells were stained with anti-BMRF1 (green) and anti-RNAPII (red). Projections of 60 images collected at 0.33-μm steps in the z axis are displayed as 3D topographical reconstruction images of BMRF1 and RNAPII (left and middle panels, respectively). Representative 3D surface reconstruction images are presented. Right panels are merged 3D surface reconstruction images. (C) The ratio of cells in which RNAPII was located outside the BMRF1 core to total BMRF1-positive cells was determined (black bars). White bars show the ratios of cells in which RNAPII was located inside the BMRF core to total BMRF1-positive cells. We regarded cells as inside when 50% or more of RNAPII signals were detected inside the core. More than 100 cells were counted at each of the indicated time points.

32 suggested that the molecular chaperone Hsp90 signal transduction, leading to promotion of viral interacts with BALF5. Treatment with Hsp90 lytic DNA replication. inhibitors blocked viral DNA replication almost completely during lytic infection, and knockdown 7. Pin1 Interacts with the Epstein-Barr of Hsp90β reduced viral genome synthesis. Virus DNA Polymerase Catalytic Subunit Collectively the results indicate that Hsp90 interacts and Regulates Viral DNA Replication with BALF5 in the cytoplasm to assist complex Narita, Y., Murata, T., Kanda, T., and Tsurumi, T. formation with BMRF1, leading to nuclear Peptidyl-prolyl cis-trans isomerase transport. Hsp90 inhibitors may be useful for NIMA-interacting 1 (Pin1) protein is known as a therapy for EBV-associated diseases in the future. regulator which recognizes phosphorylated Ser/Thr-Pro motifs and increases the rate of cis and 6. Epstein-Barr Virus Deubiquitinase trans amide isomer interconversion, thereby altering Downregulates TRAF6-mediated NF-κB the conformation of its substrates. We found that Signaling during Productive Replication Pin1 knockdown using short hairpin RNA (shRNA) Saito, S., Murata, T., Kanda, T., and Tsurumi, T. technology resulted in strong suppression of Epstein-Barr virus (EBV), a human oncogenic productive Epstein-Barr virus (EBV) DNA herpesvirus that establishes a lifelong latent replication. We further identified the EBV DNA infection in the host, occasionally enters lytic polymerase catalytic subunit, BALF5, as a Pin1 infection to produce progeny viruses. The EBV substrate in glutathione S-transferase (GST) oncogene latent membrane protein 1 (LMP1), pulldown and immunoprecipitation assays. Lambda which is expressed in both latent and lytic infection, protein phosphatase treatment abolished the binding constitutively activates the canonical NF-κB (p65) of BALF5 to Pin1, and mutation analysis of BALF5 pathway. Such LMP1-mediated NF-κB activation is revealed that replacement of the Thr178 residue by necessary for proliferation of latently infected cells Ala (BALF5 T178A) disrupted the interaction with and inhibition of viral lytic cycle progression. Pin1. To further test the effects of Pin1 in the Actually, canonical NF-κB target gene expression context of virus infection, we constructed a was found to be suppressed upon onset of lytic BALF5-deficient recombinant virus. Exogenous infection. TRAF6, which is activated by supply of wild-type BALF5 in HEK293 cells with conjugation of polyubiquitin chains, associates with knockout recombinant EBV allowed efficient LMP1 to mediate NF-κB signal transduction. We synthesis of viral genome DNA, but BALF5 T178A have established that EBV-encoded BPLF1 could not provide support as efficiently as wild-type interacts with and deubiquitinates TRAF6 to inhibit BALF5. In conclusion, we found that EBV DNA NF-κB signaling during lytic infection. Thus polymerase BALF5 subunit interacts with Pin1 HEK293 cells with BPLF1-deficient recombinant through BALF5 Thr178 in a EBV exhibited poor viral DNA replication phosphorylation-dependent manner. Pin1 might compared with the wild type. Furthermore, modulate EBV DNA polymerase conformation for exogenous expression of BPLF1 or p65 knockdown efficient, productive viral DNA replication. in cells restored DNA replication of BPLF1-deficient viruses, indicating that EBV BPLF1 deubiquitinates TRAF6 to inhibit NF-κB

Fig. 3. A schematic model demonstrating inhibition of NF-κB signaling by BPLF1 in the EBV life cycle. In EBV latent infection, NF-κB is activated by viral LMP1 protein; TRAF6 associates with LMP1 and is constitutively polyubiquitinated. Activation of NF-κB confers cell survival as well as inhibiting spontaneous lytic replication. Changes in the host cell microenvironment or other unknown triggers can downregulate the NF-κB activity and disrupt the balance between the latent cycle and the lytic cycle of EBV. Once lytic replication is induced, BPLF1 then deubiquitinates and inactivates TRAF6 to further block NF-κB signaling, promoting efficient viral genome replication.

8. HLA-restricted Presentation of WT1 reactivation of the virus from latency is dependent Tumor Antigen in B-lymphoblastoid on the expression of the viral BZLF1 protein. The Cell Lines Established using a BZLF1 promoter (Zp) normally exhibits only low Maxi-EBV System basal activity but is activated in response to Kanda, T., Kuzushima, K.*1, and Tsurumi, T. chemical or biological inducers, such as Lymphoblastoid cell lines (LCLs), which are 12-O-tetradecanoylphorbol-13-acetate (TPA), established by in vitro infection of peripheral calcium ionophores, or histone deacetylase B-lymphocytes with Epstein-Barr virus (EBV), are (HDAC) inhibitors. In some cell lines latently effective antigen-presenting cells. However, the infected with EBV, an HDAC inhibitor alone can ability of LCLs to present transduced tumor induce BZLF1 transcription, while the treatment antigens has not yet been evaluated in detail. We does not enhance expression in other cell lines, such report a single-step strategy utilizing a recombinant as B95-8 or Raji cells, suggesting unknown EBV (maxi-EBV) to convert B-lymphocytes from suppressive mechanisms besides histone any individuals into indefinitely growing LCLs deacetylation in those cells. Here, we found expressing a transgene of interest. The strategy was epigenetic modification of the BZLF1 promoter in successfully used to establish LCLs expressing latent Raji cells by histone H3 lysine 27 Wilms' tumor gene 1 (WT1) tumor antigen trimethylation (H3K27me3), H3K9me2/me3, and (WT1-LCLs), which is an attractive target for H4K20me3. Levels of active markers such as cancer immunotherapy. The established WT1-LCLs histone acetylation and H3K4me3 were low in expressed more abundant WT1 protein than K562 latent cells but increased upon reactivation. leukemic cells, which are known to overexpress Treatment with 3-deazaneplanocin A (DZNep), an WT1. A WT1-specific cytotoxic T lymphocyte line inhibitor of H3K27me3 and H4K20me3, efficiently lysed the WT1-LCL in a human significantly enhanced the BZLF1 transcription in leukocyte antigen-restricted manner, but poorly Raji cells when in combination with an HDAC lysed control LCL not expressing WT1. These inhibitor, trichostatin A (TSA). Knockdown of results indicate that the transduced WT1 antigen is Ezh2 or Suv420h1, histone methyltransferases for processed and presented on the WT1-LCL. This H3K27me3 or H4K20me3, respectively, further experimental strategy can be applied to establish proved the suppression of Zp by methylation. LCLs expressing other tumor antigens and should Taken together, the results indicate that H3K27 find a broad range of applications in the field of methylation and H4K20 methylation are involved, cancer immunotherapy. at least partly, in the maintenance of latency, and histone acetylation and H3K4 methylation correlate 9. Epigenetic Histone Modification of the with the reactivation of the virus in Raji cells. Epstein-Barr Virus BZLF1 Promoter during Latency and Reactivation in Raji *1 Division of Immunology, Aichi Cancer Center Cells Research Insutitute *2 Murata, T., Kondo, Y.*2, and Tsurumi, T. Division of Epigenomics, Aichi Cancer Center The Epstein-Barr virus (EBV) predominantly Research Insutitute establishes latent infection in B cells, and the

Fig. 4. Summary of epigenetic histone modifications in the BZLF1 promoter of Raji cells. Repressive histone H3K9, H3K27, H4K20 methylation (marked with blue circles) is present in latency, and is not appreciably decreased even after induction. High levels of active markers, such as H3K4 methylation and histone acetylation (green circles), are notably associated with lytic induction.

From left to right First row: Dr. T. Fujishita, Dr. M. Aoki, Dr. R. Kajino, Ms. Y. Goto Second row: Dr. R. Maeda, Dr. K. Sakuma, Mr. M.V.Boxtel, Dr. Y. Kojima

______Division of Molecular Pathology ______

Masahiro Aoki, M.D., D.M.Sc., Chief Keiichiro Sakuma, M.D., D.M.Sc., Senior Researcher Yasushi Kojima, M.D., D.M.Sc., Senior Researcher Rie Kajino., Ph.D. Researcher (as of April 2012) Teruaki Fujishita, D.M.Sc Researcher (as of April 2013) Yoshiko Goto, D.V.M.S., Research Assistant Ryo Maeda, M.D., Research Resident (as of April 2013)

Visiting Scientists Reiji Kannagi, M.D., D.M.Sc.

Visiting Trainees Sachiko Kondo, M.E., Nagoya City University (until March 2013) Mark van Boxtel, Radboud University Nijmegen (as of September 2013)

General Summary The incidence of colon cancer is increasing steadily in Japan; the disease is predicted to become the most common cancer as of 2020. Accumulating evidence suggests that in addition to genetic and epigenetic changes in the genome of cancer cells, interactions of cancer cells with non-cancer stromal cells play essential roles in support of colon cancer progression. Our research has aimed mainly to identify novel molecular targets for prevention and/or therapy of colon cancer through careful analyses of the intestinal tumor progression in genetically engineered mouse models, followed by evaluation of the findings using clinical samples. We are currently interested in the following subjects: (1) Genetic dissection of the signaling pathways that play pivotal roles in colon carcinogenesis; (2) Elucidating the complex tumor-stroma interactions that promote invasion and metastasis of colon cancer; (3) Identification of novel metastasis suppressor genes in colon cancer; and (4) Unraveling the pathophysiology of cancer cachexia.

1. c-Myc and CDX2 mediate E-selectin using HT29 and DLD-1 colon cancer cells. ligand glycan expression in colon Treatment of the cells with EGF and/or bFGF in the cancer cells undergoing EMT absence of fetal bovine serum dramatically induced Sakuma, K., Kannagi, R., and Aoki, M. EMT and significantly increased the sLex/a Sialyl Lewis x (sLex) and sialyl Lewis a (sLea) expression levels. The transcript levels of are E-selectin ligand glycans expressed on many ST3GAL1/3/4 and FUT3, encoding types of cancer cells including colon cancer. sialyltransferases and a fucosyltransferase, Despite their clinical usefulness as tumor markers, respectively, which directly promote sLex/a supported by the accumulating evidence showing synthesis, were elevated upon EMT, while the strong correlation between their expression levels transcript level of FUT2, encoding a and cancer progression, the mechanism underlying fucosyltransferase counteracting with their expression remains elusive. In this study, we ST3GAL1/3/4 for sLex/a synthesis, was reduced. addressed a link between the sLex/a expression Knockdown and forced expression experiments levels and epithelial-mesenchymal transition (EMT), showed that the induction of ST3GAL1/3/4 and a critical step during the progression of epithelial FUT3 was mediated by c-Myc, most likely through tumors. its phosphorylation at Ser62 during EMT, and the We first determined by immunohistochemistry suppression of FUT2 was attributed to the the sLex/a expression levels in human colon cancer attenuation of CDX2 . These results suggest a cells undergoing EMT. The results indicated a pivotal involvement of c-Myc and CDX2 in sLex/a correlation between the loss of cell-membranous expression in colon cancer cells undergoing EMT. E-cadherin and high sLea levels, supporting their link. We then addressed if there could be a common 2. CDX Transcription Factors Positively x/a mechanism underlying sLe expression and EMT, Regulate Expression of PLEKHG1 in 36

Intestinal Epithelium formation of benign intestinal adenomas in Apc∆716 *1 Aoki, M., Fujishita, T. and Taketo, MM. mice and prolonged their survival. However, we The Caudal-related homeodomain transcription noticed that long-term treatment with RAD001 factors CDX1 and CDX2 regulate development of resulted in emergence of resistant tumors that the gut, as wells differentiation of intestinal showed hyperactivation of the mTORC2 pathway. epithelial cells. The CDX transcription factors are To determine the roles of the mTORC pathways in often down-regulated in colorectal carcinomas, and formation of invasive intestinal adenocarcinomas, considered candidate tumor suppressors. A we treated cis-Apc∆716/Smad4 compound mutant chromatin immunoprecipitation (ChIP) screen mice (cis-Apc/Smad4 mice) with RAD001 identified pleckstrin homology domain containing, (everolimus), an mTORC1 selective inhibitor, or family G (with RhoGef domain) member 1 AZD8055, an ATP-competitive kinase inhibitor of (PLEKHG1) gene, a member of genes encoding mTOR. RAD001 treatment suppressed intestinal Dbl-family RhoGEFs, as a novel target of CDX1 adenocarcinoma formation and their local invasion, and CDX2. The CDX transcription factors bind to and improved their survival. While eight-week the upstream enhancer region of the PLEKHG1 treatment was required to block adenocarcinoma gene and transactivate reporter genes containing the formation with RAD001, two-week treatment with region. Overexpression of Cdx1 or Cdx2 in a AZD8055 significantly suppressed it. AZD8055 normal rat intestinal epithelial cell line markedly treatment suppressed the mTORC2 activation in induced expression of the endogenous Plekhg1, tumors of cis-Apc/Smad4 mice. Moreover, the whereas knockdowns of CDX2 reduced the phosphorylation level of 4E-BP1, a downstream PLEKHG1 transcript level in human colon cancer target of mTORC1, in tumors was greatly reduced cells. Lentivirus-mediated knockdown of by AZD8055, as compared with RAD001. These PLEKHG1 in HCT 116 colon cancer cells resulted results indicate the essential roles of the mTOR in enhanced proliferation and decreased cell-cell signaling in the growth of intestinal adhesion. Preliminary experiments using Plekhg1 adenocarcinomas as well as in adenomas, and also knockout mice show that the loss of Plekhg1 potent antineoplastic activity of the mTOR kinase +/Δ716 enhances polyp formation in the colon of Apc inhibitor against them. mice, a model for familial adenomatous polyposis (FAP) and the early stage of colon cancer *1 Department of Pharmacology, Graduate School of development. These results suggest PLEKHG1 may Medicine, Kyoto University have a tumor suppresser-like function in the colon.

*1 Department of Pharmacology, Graduate School of Medicine, Kyoto University

3. Roles of the mTOR signaling in intestinal adenocarcinoma formation in cis-Apc/Smad4 mutant mice Fujishita, T., Taketo, MM. *1 and Aoki, M. The serine/threonine kinase mTOR (mammalian target of rapamycin) forms two distinct complexes: mTORC1 (mTOR complex 1) and mTORC2. Activation of mTORC1 has been implicated in various types of human cancers. We Fig.1. Schematic representation of the suppressive previously reported that the mTORC1-specific effects of the mTORC1 inhibitor RAD001 (A) , and the inhibitor everolimus (RAD001) suppressed the mTOR kinase inhibitor AZ8055 (B), on intestinal adenocarcinoma formation in cis-Apc/Smad4 mice.

From left to right First row: Ms. Y. Takada, Dr. S. Era, Ms. K. Kobori, Dr. H. Goto, Ms. N. Tanigawa Second row: Dr. H. Tanaka, Dr. H. Inaba, Dr. M. Inagaki, Ms. E. Kawamoto, Dr. K. Kasahara, Dr. I. Izawa, Dr. Y. Hayashi, Dr. A. Inoko Inset: Dr. M. Matsuyama, Dr. D. He, Dr. Z. Wang, Ms. C. Yuhara, Ms. Y. Itoh, Dr. P. Li

______Division of Biochemistry ______

Masaki Inagaki, M.D., Ph.D. Chief Ichiro Izawa, M.D., Ph.D. Section Head Hidemasa Goto, M.D., Ph.D. Section Head Akihito Inoko, M.D., Ph.D. Senior Researcher Kousuke Kasahara, Ph.D. Researcher Yuko Hayashi, Ph.D. Research Assistant Hiroki Tanaka, D.D.S., Ph.D. Research Resident Makoto Matsuyama, Ph.D. Research Resident (until March 2012) Dongwei He, Ph.D. Research Resident (until November 2012) Zhonghua Wang, Ph.D. Research Resident (until May 2012) Hironori Inaba, Ph.D. Research Resident (as of April 2013) Saho Era, Ph.D. Research Resident (as of April 2013) Kyoko Kobori, Semi-regular Employee Eriko Kawamoto, Semi-regular Employee Naomi Tanigawa, Semi-regular Employee (as of April 2013)

Visiting Scientists Ping Li, M.D., Ph.D. Global COE Postdoctoral Fellow, Nagoya University Graduate School of Medicine

General Summary Aneuploidy, a phenotype of chromosomal instability, is a common genetic feature of solid human cancers, although it remains unclear whether as a cause or a consequence of malignant transformation. Recently, aneuploidy has been also reported to be involved in ageing. We generated knock-in mice featuring vimentin with mitotic phospho-defective mutations to impair cytokinesis. Homozygotic mice (VIMSA/SA) presented with microophthalmia and cataracts, in which lens epithelial cells exhibited chromosomal instability, including binucleation and aneuploidy, along with premature aging. VimentinSA/SA mice may offer beneficial tools to further dissect the molecular link between aneuploidy, tumorigenesis and aging. Tumor cells are known to often lack primary cilia, but whether their loss is directly linked to tumorigenesis is completely unclear. We revealed that the trichoplein-Aurora A pathway is integral to continuous suppression of primary cilia assembly, which is required for G1 cell cycle progression. In addition, we have recently found that the ubiquitin proteasome pathway is involved in the regulation of primary cilia formation. In addition, to investigate the molecular mechanisms of cell cycle progression and chromosomal instability, we have been examining the functions of kinases including Chk1, Plk1, Aurora A, and Aurora B, taking advantage of the availability of site- and phosphorylation state-specific antibodies.

1. Emerging roles of ubiquitin-proteasome through coordinated functions between positive and machinery in formation of primary cilia negative regulators of ciliogenesis. However, the Kasahara, K., Era, S., Kawamoto, E., Kawakami, Y.*1, regulatory mechanisms of ciliogenesis remain to be *2 *3 *1 Kiyono, T. , Kawamura, Y. , Goshima, N. , and disclosed in detail. Inagaki, M. The ubiquitin-proteasome system (UPS) Non-motile primary cilia are microtubule-based controls many aspects of cell physiology including sensory organelles that regulate a number of cell cycling and organelle biogenesis. In this study, signaling pathways during development and tissue we newly recognized a role of UPS in primary cilia homeostasis. Defects in primary cilia formation biogenesis. Using human cells, we could show that (ciliogenesis) result in numerous diseases and proteasome activity is essential for ciliogenesis and disorders commonly known as ciliopathies. Primary destruction of Trichoplein, a centriolar protein that cilia are grown from modified centrioles called negatively regulates ciliogenesis through activation basal bodies in response to cell cycle exit or entry of Aurora-A kinases. Trichoplein is rapidly into quiescence, and this process is achieved degraded in a polyubiquitylation-dependent fashion 39 upon serum starvation. Using protein array and There is increasing evidence that IF siRNA screens, we identified KCTD17, a protein disassembly is regulated by phosphorylation of that is required for ciliogenesis, as a ubiquitin E3 Ser/Thr residues in the amino-terminal head ligase for Trichoplein from 1172 putative E3 ligases. domains of IF proteins. Site- and phosphorylation Mechanistically, KCTD17 functions as a state-specific antibodies that can recognize a substrate-adaptor of Cul3-based ubiquitin E3 ligase phosphorylated residue and its flanking sequence that polyubiquitylates Trichoplein. SiRNA mediated are powerful tools to demonstrate site KCTD17 depletion prevented Trichoplein (domain)-specific IF phosphorylation in cells. degradation and inactivation of Aurora-A, thereby Using such antibodies, we first showed that mitotic leading to defective ciliogenesis after serum IF phosphorylation is regulated by distinct protein starvation. These phenotypes were rescued by kinases in a spatiotemporally regulated manner. expression of siRNA-resistant Myc-tagged Further detailed studies revealed that several KCTD17 or co-silencing of Trichoplein, and mitotic kinases such as Aurora-B, Cdk1, Plk1, and recapitulated by expression of non-degradable Rho-kinase, participate in mitotic phosphorylation Trichoplein mutant. Similar to KCTD17 loss, Cul3 of type III IF proteins. By transient expression of depletion also blocked ciliogenesis and Trichoplein type III IF proteins mutated at these mitotic degradation. These results indicate that phosphorylation sites to Ala in a type III Cul3-KCTD17 ubiquitin E3 ligase promotes IF-deficient T24 cell line, we found that disturbance ciliogenesis through destruction of Trichoplein. of mitotic IF phosphorylation induced abnormal IF Maintenance of normal Trichoplein levels is structures (referred as IF bridges) connecting two essential for cell cycle progression through daughter cells during the cytokinetic process. These regulating ciliogenesis, as excessive Trichoplein findings indicated that mitotic IF phosphorylation is suppresses aberrant ciliogenesis in non-proliferating essential for efficient separation of IFs into two cells, whereas its depletion leads to aberrant daughter cells. Cells with IF bridges appeared to ciliogenesis in proliferating cells. Our study reveals make two distinct decisions regarding cell fate. IF that UPS controls degradation of Trichoplein to bridges were torn off between two daughter cells, promotes ciliogenesis. We propose that UPS likely by cell-adhesion-dependent traction forces, deficiency serves as a potential underlying completion of cytokinesis resulted. The other type mechanism of ciliogenesis, and that UPS regulation of cells failed in cytokinesis, with formation of might provide a novel means of ciliopathy binucleate (multinucleate) cells. However, the treatment. significance of mitotic IF phosphorylation during organogenesis and tissue homeostasis remains *1 Molecular Profiling Research Center for Drug largely unknown. Discovery, National Institute of Advanced Industrial In the present study, we generated knock-in Science and Technology *2 mice expressing vimentin that harbor mutations in Virology Division, National Cancer Center Research mitotic phosphorylation sites. Homozygotic mice Institute SA/SA *3 (VIM ) presented with microophthalmia and Japan Biological Informatics Consortium (JBiC) lens cataracts, whereas heterozygotic mice

(VIMWT/SA) were indistinguishable from WT 2. Cytokinetic failure induces aneuploidy WT/WT SA/SA (VIM ) mice. In VIM mice, lens epithelial and aging in vimentin phosphorylation cells were reduced in number and exhibited deficient mice Tanaka, Hir., Matsuyama, M., Inoko, A., Goto, H., chromosomal instability (CIN), including *1 binucleation and aneuploidy. Electron microscopic Yonemura, S. , Kobori, K., Tanigawa, N., Hayashi, Y., SA/SA Kondo, E. *2, Itohara, S. *3, Izawa, I. and Inagaki, M. analyses revealed that lens fiber cells of VIM Intermediate filaments (IFs), together with mice exhibited membrane disorganization similar to microtubules and actin filaments, form the defects in age-related cataracts. Since the lens cytoskeletal framework in the cytoplasm of mRNA level of a senescence (aging)-related gene SA/SA eukaryotic cells. Unlike those of the two other was significantly elevated in VIM , the lens SA/SA major cytoskeletal networks, IF component proteins phenotypes in VIM suggested a possible causal are divided into six groups whose composition relationship between CIN and premature aging. generally depends on the tissue type and *1 differentiation step. On the other hand, vimentin, a Electron Microscope Laboratory, RIKEN Center for Developmental Biology type III IF protein conserved in vertebrate evolution, *2 is expressed ubiquitously in mesenchymal cells, Division of Oncological Pathology, Aichi Cancer Center Research Institute with especially high levels in lens tissue. 40

*3 Laboratory for Behavioral Genetics, RIKEN Brain centrosomes Science Institute Inoko, A., Inaba, H., He, D., Goto, H., Hayashi, Y., Izawa, I., Urano, T.*1, Yo ne mura, S.*2, Kiyono, T.*3, Goshima, *4 3. Perspective of Aurora A kinase as a N. , and Inagaki, M. therapeutic target for cancer The cell cycle is characterized by a complex set Goto, H., Watanabe, N.*1, Kobori, K., Inoko, A., of processes which lead to cell division Mochizuki, H.*2, Togashi, T. *2, Kisu, Y.*3, Kawamura, accompanied by DNA duplication. The behavior of *2 *3 *3 Y. , Kawakami, Y. , Goshima, N. , and Inagaki, M. the centrosomes, and particularly the centrioles, is Aurora A (AURKA), a centrosomal mitotic well synchronized with the cell cycle, but the kinase, controls many aspects of mitosis, such as mechanisms are not fully understood. Recently, we entry into mitosis, centrosome obtained clues from kinetics of primary cilia, that maturation/separation, and bipolar spindle protrude from mother centrioles in cultured cells, formation. Genetic amplification and protein especially in cellular quiescence. overexpression of Aurora A are observed in many We found that trichoplein, previously reported types of solid tumors and such up-regulation is as keratin-binding protein, also localizes to the associated with chromosomal instability (CIN). centrioles in proliferating cells. Interestingly, serum Aurora A kockdown (KD) or inhibition induces starvation causes ciliated mother centrioles to lose catastrophic CIN in cancerous cells, which results trichoplein. Ciliation was inhibited by exogenous in mitotic cell death (mitotic catastrophe). More expression of trichoplein. In addition, trichoplein recently, we found that phenotypes of Aurora A KD depletion was found to accelerate primary cilia are different between normal dupuloid and assembly accompanied with G1 arrest even with cancerous cells. Aurora A KD induces primary cilia serum cultivation. Notably, this G1 arrest was formation in RPE1 (normal dupuloid) cells, while reversed by a treatment for abrogating cilia. Finally, also arresting the cell cycle at the G0/G1-S it was established that the underlying mechanism is transition in a ciliation-dependent manner. On the centriolar Aurora A (AurA) activation by other hand, Aurora A KD failed to induce trichoplein in G1 phase. Thus, the trichoplein-AurA ciliogenesis or cell cycle arrest in HeLa cells, which pathway in the centrosome acts as a switch for cell have a reduced tendency to form primary cilia, like cycle progression through regulation of primary the majority of cancer cells. Based on these cilia kinetics. properties, we consider that Aurora A is a Based on this finding, we searched for similar high-value target for cancer therapeutics. proteins to trichoplein in combination with amino Now, we are employing the following 2 acid motif, determined localization, and estimated strategies to inhibit Auora A-mediated signaling functions by siRNA screening. Currently, we have pathways. One is the screening for novel Aurora A several candidate genes that mimic the phenotype inhibitors. Since Aurora A is activated through the of trichoplein depletion. Interestingly, some of them binding of Aurora A-associated proteins such as accomplished G1 arrest without primary cilia TPX2 or trichoplein (TCHP), we are now searching assembly. In this regard, it is of interest that other for small chemical(s) to inhibit their interaction. We groups previously reported that loss of centrosome have already established a high-throughput integrity induces p38–p53–p21 dependent G1-S screening system. The other is the screening for arrest, but our present phenotype is combined with novel Aurora A-interacting proteins at centrosomes intact centrosomes, suggesting the involvement of in order to identify more attactive molecular targets novel mechanisms. Investigation of the underlying downstream of Aurora A. We have already obtained mechanisms are ongoing. evidence for several putative Aurora A binding proteins, using protein arrays. We believe that these *1 Department of Biochemistry, Shimane University approaches will help to establish novel molecular School of Medicine targeted therapies. *2 RIKEN Center for Developmental Biology *3 Virology Division, National Cancer Center Research *1 RIKEN, Bioprobe Application Research Unit, Japan Institute *4 *2 Japan Biological Informatics Consortium (JBiC), Molecular Profiling Research Center for Drug Japan Discovery, National Institute of Advanced Industrial *3 Molecular Profiling Research Center for Drug Science and Technology, Japan Discovery, National Institute of Advanced Industrial Science and Technology, Japan 5. Interaction of Cell Polarity Regulator Scribble with Multidrug Resistance 4. Novel cell cycle regulation through Protein 4 (MRP4/ABCC4) 41

Izawa, I., Hayashi, Y., and Inagaki, M. revealed direct binding to the first PDZ domain Scribble, originally identified as a tumor (PDZ1) of Scribble through its C-terminus. By suppressor in Drosophila, has been implicated in coimmunoprecipitation assays, we confirmed the regulation of many aspects of cellular interaction of endogenous MRP4 and Scribble. physiology, including apical-basal cell polarity, Immunofluorescence further revealed Scribble migration, proliferation, and vesicle trafficking. To co-localization with MRP4 at basolateral further elucidate the functions of human Scribble, membranes. In Caco-2 and LNCaP cells, depletion we performed a yeast two-hybrid screen to search of Scribble by siRNAi impaired the plasma for binding partners and identified Multidrug membrane localization of MRP4. These results Resistance Protein 4 (MRP4/ABCC4) as one suggest that Scribble may affect drug resistance potential example. MRP4 is a transmembrane through regulation of basolateral membrane protein which is involved in substrate-specific targeting of MRP4. transport of endogenous and exogenous substrates, including anti-cancer drugs. In vitro binding assays

From left to right First row: Mr. Isogai S, Dr. Tojo M, Dr. Shinjo K, Dr. Kondo Y, Ms. Kitao M, Ms. Sasaki A, Ms. Takagi N Second row: Dr. Katsushima K, Dr. Ichimura N, Dr. Ohka F, Dr. Hatanaka A, Mr. Oiwa Y, Dr. Tu M

______Division______of Epigenomics ______

Yutaka Kondo M.D., Ph.D., Chief Keiko Shinjo, M.D., Ph.D., Senior Researcher Michiko Kitao, Semi-regular Employee Nami Takagi, Semi-regular Employee Akiko Sasaki, Semi-regular Employee Yuki Oiwa, Semi-regular Employee

Research Resident Humiharu Ohka, M.D., Ph.D. Keisuke Katsushima, Ph.D. Akira Hatanaka, Ph.D.

Visiting Trainees Norihisa Ichimura, D.D.S., Nagoya University School of Medicine Masayuki Tojo, M.D., Showa University School of Medicine Shinya Sato, M.D., Ph.D., Nagoya City University School of Medicine Kota Ishikawa, M.D., Nagoya University School of Medicine Shuntaro Isogai, Nagoya City University School of Medicine Min Tu, M.D., Ph.D., Nanjing Medical University Yasuyuki Okamoto, M.D., Ph.D., Nagoya City University School of Medicine (until September 2013)

General Summary Alongside known genetic changes, aberrant epigenetic alteration has emerged as common hallmark of many cancers. Epigenetic mechanisms are important in tumor progression but also possibly in tumor formation. Early detection of cancer-specific epigenetic alterations as well as therapies targeted at specific epigenetic regulators or their effectors may improve patient outcomes. Since the clinical impact of biomarkers is dependent on the stability of the information provided, DNA methylation is an ideal biomarker for cancer diagnosis. We explored the epigenetic landscapes in many types of cancers and found that DNA methylation of certain genes predominantly reflects the characteristic clinicopathological features of tumors. In order to apply these markers for clinical use, we have invented a novel and highly sensitive technology to detect methylated DNA in samples obtained through less invasive procedures, such as serum. Cancers are mostly comprised of heterogeneous cell populations. A significant degree of morphological and lineage heterogeneity may contribute to tumor invasion, metastasis and drug resistance. Since the epigenome may act at the top of the hierarchy of gene control mechanisms, dysregulation of epigenetics essentially has effects on multiple pathways relevant to the cancer phenotype. Cancer stem cells (CSC) may usurp a plastic epigenetic mechanism as a mediator of adaptation to their environment, which can contribute to tumor heterogeneity. Our works is focused on dynamic epigenetic mechanisms in cancers, their relationship with aberrant gene expression, and their potential for applications in drug discovery. In particular, we are targeting epigenetic plasticity, a challenging potentially effective approach for cancer treatment.

1. The PRC2 chromatin regulator is a key underlying mechanisms, we examined glioma regulator of epigenetic plasticity in stem-like cells (GSC) where we found that biologic glioblastoma interconversion between GSCs and differentiated Natsume, A.*1, Ito, M.*1, Katsushima, K., Ohka, F., non-GSCs is functionally plastic and accompanied *2 *3 *3 Hatanaka, A., Shinjo, K. , Sato, S. , Takahashi, S. , by gain or loss of polycomb repressive complex 2 *4 *4 *5 Ishikawa, Y. , Takeuchi, I. , Shimogawa, H. , Uesugi, (PRC2), a complex that modifies chromatin *5 *6 *7 *1 M. , Okano, H. , Kim, SU. , Wakabayashi, T. , Issa, structure. PRC2 mediates lysine 27 trimethylation JP.*8, Sekido, Y.*9, and Kondo, Y. on histone H3 and in GSCs it affects pluripotency Tumor cell plasticity contributes to functional or development-associated genes (e.g., Nanog, and morphologic heterogeneity. To uncover the 44

Fig. 1. Targets of PRC2-mediated H3K27me3 during phenotypic conversion of GSCs and S-BTCs. A, Convertible Nestin promoter activity in 1228-GSCs-pE-Nes. GSC lines stably expressing the GFP under the Nestin promoter using a pE/nestin:EGFP construct (GSC-pE-Nes) were generated. 1228-GSCs-pE-Nes lost EGFP expression by 96 hours in serum-containing culture, and re-expressed EGFP following return to NBE for 72 hours. Bar, 100 μm. B, H3K27me3 enrichment at BMP5 and Wnt1 promoters in GSCs and S-BTCs. The y axis represents enrichment of H3K27me3 (relative value of H3K27me3 to H3). C, Brain-slice assays. 1228-GSCs transduced with either mock control (Ctrl), EZH2-shRNA (EZH2 KD), Wnt1-shRNA (Wnt1 KD) or BMP5-overexpression (BMP5-expression) were placed in the basal ganglia of nude mice for 14 days (top panel). From immunofluorescence images (middle panel), expression indices of GFAP and Nestin were Wnt1, and BMP5) together with alterations in the calculated (bottom panel). The Y axis indicates subcellular localization of EZH2, a catalytic values of (Intensity-background, mean ± SD) x ROI. component of PRC2. Intriguingly, exogenous D, 1228-GSCs-pE-Nes were cultured for 7 days on expression of EZH2-dNLS, which lacks nuclear mouse brain slices. Dashed line indicates border of sphere. Arrowheads indicate differentiated tumor localization sequence, impaired the repression of cells spread into the surrounding brain tissue. The Nanog expression under differentiation conditions. areas (a) and (b) in the merged image (bottom left) RNA interference (RNAi)-mediated attenuation or are magnified in panels (a) and (b). pharmacologic inhibition of EZH2 had little to no effect on apoptosis or bromodeoxyuridine Biology, Nagoya City University Graduate School of incorporation in GSCs, but it disrupted morphologic Medical Sciences *4 interconversion and impaired GSC integration into Department of Scientific and Engineering Simulation, Graduate School of Engineering, Nagoya Institute of brain tissue, thereby improving survival of Technology GSC-bearing mice. Pathologic analysis of human *5 Institute for Integrated Cell-Material Sciences/ Institute glioma specimens revealed that the number of for Chemical Research, Kyoto University tumor cells with nuclear EZH2 is larger around *6Department of Physiology, Keio University School of tumor vessels and at invasive fronts, suggesting that Medicine nuclear EZH2 may help reprogram tumor cells in *7Division of Neurology, Department of Medicine, close proximity to particular microenvironments. University of British Columbia, Vancouver, Canada; Our results indicate that epigenetic regulation by Medical Research Institute, Chungang University PRC2 is a key mediator of tumor cell plasticity, College of Medicine *8 which is required for the adaptation of glioblastoma Fels Institute for Cancer and Molecular Biology Temple University cells to their microenvironment. Thus, *9Division of Molecular Oncology, Aichi Cancer Center PRC2-targeted therapy may reduce tumor cell Research Institute plasticity and tumor heterogeneity, offering a new paradigm for glioma treatment. 2. Hepatitis Virus Infection Affects DNA

Methylation in Mice with Humanized *1Department of Neurosurgery, Nagoya University Livers. School of Medicine Okamoto Y, Shinjo K*1, Shimizu Y*2, Sano T*2, Yamao *2Division of Oncological Pathology, Aichi Cancer K*3, Gao W*4, Fujii M*5, Osada H*5, Sekido Y*5, Center Research Institute Murakami S*6, Tanaka Y*6, Joh T*7, Sato S*8, Takahashi *3Department of Experimental Pathology and Tumor S*8, Wakita T*9, Zhu J*10, Issa JP*11, and Kondo Y. 45

Cells of tumors associated with chronic mice. There were changes in 160±63 genes in inflammation frequently have altered patterns of HBV-infected and 237±110 genes in HCV-infected DNA methylation, including hepatocellular mice. Methylation of 149 common genes increased carcinomas (HCCs). Chronic hepatitis has also been in HBV- and HCV-infected mice; methylation of associated with aberrant DNA methylation, but little some of these genes also increased in HCC samples is known about their relationship. Pyrosequencing from patients, compared with non-tumor tissues. was used to determine the methylation status of Expression of Ifng, which is expressed by natural cultured Huh7.5.1 hepatoma cells following killer (NK) cells, increased significantly in chimeric hepatitis C virus (HCV) infection. We also studied livers, in concordance with induction of DNA mice with severe combined immunodeficiency methylation, after infection with HBV or HCV. carrying the urokinase-type plasminogen activator Induction of Ifng was reduced following transgene controlled by an albumin promoter administration of an inhibitor of NK cell function (uPA/SCID mice), in which up to 85% of (anti-asialo GM1). In chimeric mice with hepatocytes were replaced by human hepatocytes humanized livers, infection with HBV and HCV (chimeric mice). Mice were given intravenous appear to activate an NK cell-dependent innate injections of hepatitis B virus (HBV) or HCV; liver immune response. This contributes to the induction tissues were collected and DNA methylation and accumulation of aberrant DNA methylation in profiles were determined at different time points human hepatocytes. after infection. We also compared methylation patterns between paired samples of HCC and *1Division of Oncological Pathology, Aichi Cancer adjacent non-tumor liver tissues from patients. No Center Research Institute *2 reproducible changes in DNA methylation were Department of Gastroenterological Surger, Aichi observed following infection of Huh7.5.1 cells with Cancer Center Hospital *3Department of Gastroenterology, Aichi Cancer Center HCV. Livers from HBV- and HCV-infected mice Hospital had genome-wide, time-dependent changes in DNA *4 Department of General Surgery, the First Affiliated methylation, compared with uninfected uPA/SCID Hospital of Nanjing Medical University *5Division of Molecular Oncology, Aichi Cancer Center Research Institute *6Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences *7Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences *8Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences *9Department of Virology II, National Institute of Infectious Diseases

Fig. 2. Hepatitis Virus Infection Affects DNA Methylation in Mice with Humanized Livers. Recent technological advances have enabled development of severe combined immunodeficiency (SCID) mice carrying a urokinase-type plasminogen activator (uPA) transgene controlled by an albumin promoter (uPA/SCID), in which the liver is repopulated with human hepatocytes (human hepatocyte chimeric mice). This mouse model features severe combined immunodeficiency due to lack of both T- and B-cell, but with normal macrophages and natural killer cell (NK cell) activity, which are important components of the innate immune system. Since both HBV and HCV can infect human hepatocytes but not murine hepatocytes, this model is a useful tool for mimicking and unraveling hepatitis virus-host interactions in vivo. Using this model, we demonstrated here that DNA methylation was induced in human hepatocytes after HBV and HCV infection, and that induction of DNA methylation was closely associated with NK cell activity.

*10Cancer Epigenetics Program, Shanghai Cancer Institute, Shanghai Jiaotong University *11Fels Institute for Cancer Research and Molecular

Biology, Temple University School of Medicine

AACR-JCA meeting 2013

From left to right Dr. M. Inagaki, Dr. H. Kumimoto, Mr. Y. Minoura, Mr. Y. Nishikawa, Ms. Y. Shinohara, and Dr. H. Nakamura

______Central Service Unit ______

Masaki Inagaki, M.D. Chief Hiroshi Kumimoto, Ph.D. Senior Researcher Yasushi Minoura, B.P., Senior Research Assistant Harunari Tanaka, B.P. Research Assistant (until March 2012) Hiromu Nakamura, D.M.Sc. Senior Semi-regular Research Assistant Yasuhiro Nishikawa, Semi-regular Research Assistant Yoshimi Shinohara, Semi-regular Employee (as of August 2013)

Visiting Trainees Erika Ito, M.D. School of Medicine, Nagoya City University

General Summary Our main research project is molecular epidemiologic analysis of human esophageal cancer. Especially, we have focused on the relationship between numbers of polymorphisms in the D-loop region of mitochondrial DNA (mtDNA) and risk of esophageal cancer development.

1. Relationship between risk of levels in cells, which would be expected to increase esophageal cancer and the number the risk of introducing mutations into mtDNA and of polymorphisms in mitochondrial genomic DNA. We therefore analyzed the number DNA of polymorphisms in mtDNA as a surrogate marker Kumimoto, H. for ROS, then evaluating the relationship with risk Mitochondria are well known as the organelles of esophageal cancer. in human for production of energy for cells and also We performed sequencing analysis of D-loop they have roles in apoptosis. Recently, frequent region in mtDNA using DNA samples from mutations have been found in various types of esophageal cancer subjects and non-cancer controls cancer, including examples in the breast and collected in the HERPACC study. At first, we stomach. Our previous analysis of mutations in used re-sequencing primers sets made by ABI, the D-loop region of mitochondrial DNA (mtDNA) mitoSEQr. We found that the whole D-loop in esophageal tumors demonstrated frequent region could be sequenced with 4 of 8 primer sets. somatic mutations (in 34 % of cases). We also After sequencing the whole D-loop region, we determined nuclear genomic instability, but did not identified polymorphisms by comparing these find any correlation with somatic mtDNA mutations, sequences with the common mtDNA sequence. suggesting that instability of mtDNA in esophageal So far, we have completed analyses of cancer might be an independent of nuclear genomic polymorphisms in 33 subjects with esophageal instability. cancer and 64 non-cancer controls (see Table 1). Energy as ATP is produced in mitochondria with After analyses of polymorphisms in 185 esophageal reactive oxygen species (ROS) as a byproduct. cancer patients and 185 non-cancer controls, we Polymorphisms in the genes related to oxidative will evaluate the relationship between esophageal phosphorylation may elevate ROS production by cancer risk and number of mitochondrial leaking electrons. Therefore the number of polymorphisms. polymorphisms in mtDNA may influence ROS

Table 1. Summary of analyses of polymorphism in mtDNA

Data are shown as average numbers / subject except 'number of subjects analyzed'.

______Librarians ______

From left to right Ms. T. Yasuda, Ms. T. Shibata, Mr. T. Matsunaga, Ms. M. Sakou, Ms. N. Terashima

______Publications ______L., Barrowdale, D., Lee, A., Healey, S., Lush, M., Journals Tessier, D., Vincent, D., Bacot, F., Australian Cancer Study, Australian Ovarian Cancer Study Group, Vergote, I., Lambrechts, S., Despierre, E., J001. Abe, S., Morita, Y., Kaneko, M.K., Risch, H., Gonzlez-Neira, A., Rossing, M., Pita, G., Hanibuchi, M., Tsujimoto, Y., Goto, H., Kakiuchi, Doherty, J., Dvarez, N., Larson, M., Fridley, B., S., Aono, Y., Huang, J., Sato, S., Kishuku, M., Schoof, N., Chang-Claude, J., Cicek, M., Peto, J., Taniguchi, Y., Azuma, M., Kawazoe, K., Sekido, Y., Kalli, K., Broeks, A., Armasu, S., Schmidt, M., Yano, S., Akiyama, S., Sone, S., Minakuchi, K., Braaf, L., Winterhoff, B., Nevanlinna, H., Kato, Y., Nishioka, Y.: A novel targeting therapy of Konecny, G., Lambrechts, D., Rogmann, L., Gunel, malignant mesothelioma using anti-podoplanin P., Teoman, A., Milne, R., Garcia, J., Cox, A., antibody. J Immunol, 190: 6239-6249, 2013. Shridhar, V., Burwinkel, B., Marme, F., Hein, R., (PMID: 23690472) Sawyer, E., Haiman, C., Wang-Gohrke, S., J002. Akatsuka, S., Yamashita. Y., Ohara, H., Liu, Andrulis, I., Moysich, K., Hopper, J., Odunsi, K., Y., Izumiya, M., Abe, K., Ochiai, M., Jiang, L., Lindblom, A., Giles, G., Brenner, H., Simard, J., Nagai, H., Okazaki, Y., Murakami, H., Sekido, Y., Lurie, G., Fasching, P., Carney, M., Radice, P., Arai, E., Kanai, Y., Hino, O., Takahashi, T., Wilkens, L., Swerdlow, A., Goodman, M., Brauch, Nakagama, H., Toyokuni, S.: Fenton reaction H., Garca-Closas, M., Hillemanns, P., Winqvist, R., induced cancer in wild type rats recapitulates Drst, M., Devilee, P., Runnebaum, I., Jakubowska, genomic alterations observed in human cancer. A., Lubinski, J., Mannermaa, A., Butzow, R., PLoS One, 7: e43403, 2012. (PMID: 22952676) Bogdanova, N., Drk, T., Pelttari, L., Zheng, W., J003. Akita, K., Yoshida, S., Ikehara, Y., Leminen, A., Anton-Culver, H., Bunker, C., Kristensen, V., Ness, R., Muir, K., Edwards, R., Shirakawa, S., Toda, M., Inoue, M., Kitawaki, J., Nakanishi, H., Narimatsu, H., Nakada, H.: Meindl, A., Heitz, F., Matsuo, K., Bois, A., Wu, A., Different levels of sialyl-Tn antigen expressed on Harter, P., Teo, S., Schwaab, I., Shu, X., Blot, W., MUC16 in patients with endometriosis and ovarian Hosono, S., Kang, D., Nakanishi, T., Hartman, M., cancer. Int J Gynecol Cancer, 22: 531-538, 2012 Yatabe, Y., Hamann, U., Karlan, B., Sangrajrang, (PMID: 22367369) S., Kjaer, S., Gaborieau, V., Jensen, A., Eccles, D., Hgdall, E., Shen, C., Brown, J., Woo, Y., Shah, M., J004. Arita, K., Maeda-Kasugai, Y., Ohshima, K., Mat, Adenan, N., Luben, R., Omar, S., Czene, K., Tsuzuki, S., Suguro-Katayama, M., Karube, K., Vierkant, R., Nordestgaard, B., Flyger, H., Vachon, Yoshida, N., Sugiyama, T., Seto, M.: Generation of C., Olson, J., Wang, X., Levine, D., Rudolph, A., mouse models of lymphoid neoplasm using Weber, R., Flesch-Janys, D., Iversen, E., Nickels, retroviral gene transduction of in vitro-induced S., Schildkraut, J., Dos-Santos-Silva, I., Cramer, germinal center B and T cells. Exp Hematol, 41: D., Gibson, L., Terry, K., Fletcher, O., Vitonis, A., 731-41.e9, 2013. (PMID: 23583576) van der Schoot, E., Poole, E., Hogervorst, F., J005. Asai, H., Fujiwara, H., An, J., Ochi, T., Tworoger, S., Liu, J., Bandera, E., Li, J., Olson, S., Miyazaki, Y., Nagai, K., Okamoto, S., Mineno, J., Humphreys, K., Orlow, I., Blomqvist, C., Kuzushima, K., Shiku, H., Inoue, H., Yasukawa, Rodriguez-Rodriguez, L., Aittomki, K., Salvesen, M.: Co-introduced functional CCR2 potentiates in H., Muranen, T., Wik, E., Brouwers, B., Krakstad, vivo anti-lung cancer functionality mediated by T C., Wauters, E., Halle, M., Wildiers, H., Kiemeney, cells double gene-modified to express WT1-specific L., Mulot, C., Aben, K., Laurent-Puig, P., van T-cell receptor. PLoS One, 8: e56820, 2013. Altena, A., Truong, T., Massuger, L., Benitez, J., (PMID: 23441216) Pejovic, T., Arias, Perez, J., Hoatlin, M., Zamora, M., Cook, L., Balasubramanian, S., Kelemen, L., J006. Bojesen, S., Pooley, K., Johnatty, S., Beesley, Schneeweiss, A., Le, N., Sohn, C., Brooks-Wilson, J., Michailidou, K., Tyrer, J., Edwards, S., Pickett, A., Tomlinson, I., Kerin, M., Miller, N., Cybulski, H., Shen, H., Smart, C., Hillman, K., Mai, P., C., kConFab Investigators, Henderson, B., Lawrenson, K., Stutz, M., Lu, Y., Karevan, R., Menkiszak, J., Schumacher, F., Wentzensen, N., Woods, N., Johnston, R., French, J., Chen, X., Le Marchand, L., Yang, H., Mulligan, A., Glendon, Wesicher, M., Nielsen, S., Maranian, M., G., Engelholm, S., Knight, J., Hgdall, C., Apicella, Ghoussaini, M., Ahmed, S., Baynes, C., C., Gore, M., Tsimiklis, H., Song, H., Southey, M., Humphreys, M., Wang, J., Dennis, J., McGuffog, 51

Jager, A., van den Ouweland, A., Martens, J., Foretova, L., Savage, S., Lester, J., Soucy, P., Flanagan, J., Kriege, M., Paul, J., Margolin, S., Kuchenbaecker, K., Olswold, C., Cunningham, J., Siddiqui, N., Severi, G., Whittemore, A., Baglietto, Slager, S., Pankratz, V., Dicks, E., Lakhani, S., L., McGuire, V., Stegmaier, C., Sieh, W., Mller, H., Couch, F., Hall, P., Gayther, S., Pharoah, P., Arndt, V., LabrChe, F., Gao, Y., Goldberg, M., Reddel, R., Goode, E., Greene, M., Easton, D., Yang, G., Dumont, M., McLaughlin, J., Hartmann, Berchuck, A., Antoniou, A., Chenevix-Trench, G., A., Ekici, A., Beckmann, M., Phelan, C., Lux, M., Dunning, A.: Multiple independent TERT variants Permuth-Wey, J., Peissel, B., Sellers, T., Ficarazzi, associated with telomere length and risks of breast F., Barile, M., Ziogas, A., Ashworth, A., and ovarian cancer. Nat Genet, 45: 371-384, 2013. Gentry-Maharaj, A., Jones, M., Ramus, S., Orr, N., (PMID: 23535731) Menon, U., The Genica Network, Pearce, C., J007. Chew, S.H., Okazaki, Y., Nagai, H., Misawa, Brning, T., Pike, M., Ko, Y., Lissowska, J., N., Akatsuka, S., Yamashita, K., Jiang, L., Figueroa, J., Kupryjanczyk, J., Chanock, S., Yamashita, Y., Noguchi, M., Hosoda, K., Sekido, Y., Dansonka-Mieszkowska, A., Jukkola-Vuorinen, A., Takahashi, T., Toyokuni, S.: Cancer-promoting role Rzepecka, I., Pylks, K., Bidzinski, M., Kauppila, S., of adipocytes in asbestos-induced mesothelial Hollestelle, A., Seynaeve, C., Monteiro, A., carcinogenesis through dysregulated adipocytokine Tollenaar, R., Durda, K., Jaworska, K., production. Carcinogenesis, 2013 Sep 10, [Epub Hartikainen, J., Kosma, V., Kataja, V., ahead of print] (PMID: 23917077) Antonenkova, N., Long, J., Shrubsole, M., Deming-Halverson, S., Lophatananon, A., J008. Chihara, D., Ito, H., Katanoda, K., Shibata, Siriwanarangsan, P., Stewart-Brown, S., Ditsch, A., Matsuda, T., Tajima, K., Sobue, T., Matsuo, K.: N., Lichtner, P., Schmutzler, R., Ito, H., Iwata, H., Increase in incidence of adult T-cell Tajima, K., Tseng, C., Stram, D., den, D., Yip, C., leukemia/lymphoma in non-endemic areas of Japan Ikram, M., The, Y., Cai, H., Lu, W., Signorello, L., and the United States. Cancer Sci, 103: 1857-1860, Cai, Q., Noh, D., Yoo, K., Miao, H., Iau, P., Teo, Y., 2012. (PMID: 22738276) McKay, J., Shapiro, C., Ademuyiwa, F., Fountzilas, J009. Chihara, D., Ito, H., Matsuda, T., Katanoda, G., Hsiung, C., Yu, J., Hou, M., Healey, C., K., Shibata, A., Saika, K., Sobue, T., Matsuo, K.: Luccarini, C., Wang, Q., Peock, S., Decreasing trend in mortality of chronic Stoppa-Lyonnet, D., Peterlongo, P., SWE-BRCA, myelogenous leukemia patients after introduction of Rebbeck, T., Piedmonte, M., Singer, C., Friedman, imatinib in Japan and the U.S. Oncologist, 17: E., Thomassen, M., Offit, K., Hansen, T., 1547-1550, 2012. (PMID: 22971523) Neuhausen, S., Szabo, C., Blanco, I., Garber, J., Narod, S., Weitzel, J., Montagna, M., Olah, E., J010. Chihara, D., Matsuo, K., Kanda, J., Hosono, Godwin, A., Yannoukakos, D., Goldgar, D., Caldes, S., Ito, H., Nakamura, S., Seto, M., Morishima, Y., T., Imyanitov, E., Tihomirova, L., Arun, B., Tajima, K., Tanaka, H.: Inverse association Campbell, I., Mensenkamp, A., van Asperen, C., between soy intake and non-Hodgkin lymphoma van Roozendaal, K., Meijers-Heijboer, H., risk among women: a case-control study in Japan. HEBON, Colle, J., Oosterwijk, J., Hooning, M., Ann Oncol, 23: 1061-1066, 2012. (PMID: Rookus, M., van der Luijt, R., van Os, T., Evans, 21765045) D., Frost, D., Fineberg, E., Embrace, Barwell, J., J011. Chuang, S.C., Jenab, M., Heck, J.E., Bosetti, Walker, L., Kennedy, M., Platte, R., Davidson, R., C., Talamini, R., Matsuo, K., Castellsague, X., Ellis, S., Cole, T., de Paillerets, B., Buecher, B., Franceschi, S., Herrero, R., Winn, D.M., La, Damiola, F., Collaborators, G., Faivre, L., Frenay, Vecchia, C., Morgenstern, H., Zhang, Z.F., Levi, M., Sinilnikova, O., Caron, O., Giraud, S., F., Dal, Maso, L., Kelsey, K., McClean, M.D., Mazoyer, S., Bonadona, V., Caux-Moncoutier, V., Vaughan, T., Lazarus, P., Muscat, J., Ramroth, H., Toloczko-Grabarek, A., Gronwald, J., Byrski, T., Chen, C., Schwartz, S.M., Eluf-Neto, J., Hayes, Spurdle, A., Bonanni, B., Zaffaroni, D., Giannini, R.B., Purdue, M., Boccia, S., Cadoni, G., Zaridze, G., Bernard, L., Dolcetti, R., Manoukian, S., D., Koifman, S., Curado, M.P., Ahrens, W., Norbert, A., Engel, C., Helmut, D., Rhiem, K., Benhamou, S., Matos, E., Lagiou, P., Alfons, M., Dieter, N., Hansjoerg, P., Christian, S., Szeszenia-Dabrowska, N., Olshan, A.F., Wappenschmidt, B., Borg, A., Melin, B., Rantala, Fernandez, L., Menezes, A., Agudo, A., Daudt, J., Soller, M., Nathanson, K., Domchek, S., A.W., Merletti, F., Macfarlane, G.J., Kjaerheim, K., Rodriguez, G., Salani, R., Kaulich, D., Tea, M., Mates, D., Holcatova, I., Schantz, S., Yu, G.P., Paluch, S., Laitman, Y., Skytte, A., Kruse, T., Simonato, L., Brenner, H., Mueller, H., Conway, Jensen, U., Robson, M., Gerdes, A., Ejlertsen, B., 52

D.I., Thomson, P., Fabianova, E., Znaor, A., J018. French, J.D., Ghoussaini, M., Edwards, S.L., Rudnai, P., Healy, C.M., Ferro, G., Brennan, P., Meyer, K.B., Michailidou, K., Ahmed, S., Khan, S., Boffetta, P., Hashibe, M.: Diet and the risk of head Maranian, M.J., O'Reilly, M., Hillman, K.M., and neck cancer: a pooled analysis in the Betts, J.A., Carroll, T., Bailey, P.J., Dicks, E., INHANCE consortium. Cancer Cause Control, 23: Beesley, J., Tyrer, J., Maia, A.T., Beck, A., 69-88, 2012 (PMID: 22037906) Knoblauch, N.W., Chen, C., Kraft, P., Barnes, D., Gonzlez-Neira, A., Alonso, M.R., Herrero, D., J012. De, Feo, E., Simone, B., Kamgaing, R.S., Tessier, D.C., Vincent, D., Bacot, F., Luccarini, C., Gallì, P., Hamajima, N., Hu, Z., Li, G., Li, Y., Baynes, C., Conroy, D., Dennis, J., Bolla, M.K., Matsuo, K., Park, J.Y., Roychoudhury, S., Spitz, Wang, Q., Hopper, J.L., Southey, M.C., Schmidt, M.R., Wei, Q., Zhang, J.H., Ricciardi, W., Boccia, M.K., Broeks, A., Verhoef, S., Cornelissen, S., S.: p73 G4C14-to-A4T14 gene polymorphism and Muir, K., Lophatananon, A., Stewart-Brown, S., interaction with p53 exon 4 Arg72Pro on cancer Siriwanarangsan, P., Fasching, P.A., Loehberg, susceptibility: a meta-analysis of the literature. C.R., Ekici, A.B., Beckmann, M.W., Peto, J., Dos Mutagenesis, 27: 267-273, 2012. (PMID: Santos Silva, I., Johnson, N., Aitken, Z., Sawyer, 21976716) E.J., Tomlinson, I., Kerin, M.J., Miller, N., Marme, J013. Demachi-Okamura, A., Torikai, H., F., Schneeweiss, A., Sohn, C., Burwinkel, B., Akatsuka, Y., Miyoshi, H., Yoshimori, T., Gunel, P., Truong, T., Laurent-Puig, P., Menegaux, Kuzushima, K.: Autophagy creates a CTL epitope F., Bojesen, S.E., Nordestgaard, B.G., Nielsen, S.F., that mimics tumor-associated antigens. PLoS One, Flyger, H., Milne, R.L., Zamora, M.P., Arias Perez, 7: e47126, 2012. (PMID: 23071732) J.I., Benitez, J., Anton-Culver, H., Brenner, H., J014. Duverle, D.A., Takeuchi, I., Mller, H., Arndt, V., Stegmaier, C., Meindl, A., Murakami-Tonami, Y., Kadomatsu, K., Tsuda, K.: Lichtner, P., Schmutzler, R.K., Engel, C., Brauch, Discovering Combinatorial Interactions in Survival H., Hamann, U., Justenhoven, C; The GENICA Data. Bioinformatics, 2013 Sep 13, [Epub ahead of Network, Aaltonen, K., Heikkil, P., Aittomki, K., print] (PMID: 24037215) Blomqvist, C., Matsuo, K., Ito, H., Iwata, H., Sueta, A., Bogdanova, N.V., Antonenkova, N.N., Drk, T., J015. Eikawa, S., Kakimi, K., Isobe, M., Lindblom, A., Margolin, S., Mannermaa, A., Kuzushima, K., Luescher, I., Ohue, Y., Ikeuchi, K., Kataja, V., Kosma, V.M., Hartikainen, J.M.; Uenaka, A., Nishikawa, H., Udono, H., Oka, M., kConFab Investigators, Wu, A.H., Tseng, C.C., Nakayama, E.: Induction of CD8 T-cell responses Van Den Berg, D., Stram, D.O., Lambrechts, D., restricted to multiple HLA class I alleles in a cancer Peeters, S., Smeets, A., Floris, G., Chang-Claude, patient by immunization with a 20-mer NY-ESO-1f J., Rudolph, A., Nickels, S., Flesch-Janys, D., (NY-ESO-1 91-110) peptide. Int J Cancer, 132: Radice, P., Peterlongo, P., Bonanni B, Sardella D, 345-354, 2013. (PMID: 22729530) Couch FJ, Wang X, Pankratz VS, Lee A, Giles GG, J016. Elshazley, M., Sato, M., Hase, T., Takeyama, Severi G, Baglietto, L., Haiman, C.A., Henderson, Y., Yamashita, R., Yoshida, K., Toyokuni, S., B.E., Schumacher, F., Le Marchand, L., Simard, Ishiguro, F., Osada, H., Sekido, Y., Yokoi, K., J., Goldberg, M.S., Labrche, F., Dumont, M., Teo, Usami, N., Shames, D.S., Kondo, M., Gazdar, A.F., S.H., Yip, C.H., Ng, C.H., Vithana, E.N., Minna, J.D., Hasegawa, Y.: The circadian clock Kristensen, V., Zheng, W., Deming-Halverson, S., gene BMAL1 is a novel therapeutic target for Shrubsole, M., Long, J., Winqvist, R., Pylks, K., malignant mesothelioma. Int J Cancer, 131: Jukkola-Vuorinen, A., Grip, M., Andrulis, I.L., 2820-2831, 2012. (PMID: 22510946) Knight, J.A., Glendon, G., Mulligan, A.M., Devilee, P., Seynaeve, C., Garca-Closas, M., Figueroa, J., J017. Fan, Q., Barathi, V.A., Cheng, C.Y., Zhou, Chanock, S.J., Lissowska, J., Czene, K., X., Meguro, A., Nakata, I., Khor, C.C., Goh, L.K., Klevebring, D., Schoof, N., Hooning, M.J., Li, Y.J., Lim, W., Ho, C.E., Hawthorne, F., Zheng, Martens, J.W., Colle, J.M., Tilanus-Linthorst, M., Y., Chua, D., Inoko, H., Yamashiro, K., Hall, P., Li, J., Liu, J., Humphreys, K., Shu, X.O., Ohno-Matsui, K., Matsuo, K., Matsuda, F., Lu, W., Gao, Y.T., Cai, H., Cox, A., Vithana, E., Seielstad, M., Mizuki, N., Beuerman, Balasubramanian, S.P., Blot, W., Signorello, L.B., R.W., Tai, E.S., Yoshimura, N., Aung, T., Young, Cai, Q., Pharoah, P.D., Healey, C.S., Shah, M., T.L., Wong, T.Y., Teo, Y.Y., Saw, S.M.: Genetic Pooley, K.A., Kang, D., Yoo, K.Y., Noh, D.Y., variants on chromosome 1q41 influence ocular Hartman, M., Miao, H., Sng, J.H., Sim, X., axial length and high myopia. PLoS Genet, 8: Jakubowska, A., Lubinski, J., Jaworska-Bieniek, e1002753, 2012. (PMID: 22685421) K., Durda, K., Sangrajrang, S., Gaborieau, V., 53

McKay, J., Toland, A.E., Ambrosone, C.B., Silva, I., Johnson, N., Warren, H., Tomlinson, I., Yannoukakos, D., Godwin, A.K., Shen, C.Y., Kerin, M.J., Miller, N., Marme, F.,Schneeweiss, Hsiung, C.N., Wu, P.E., Chen, S.T., Swerdlow, A., A., Sohn, C., Truong, T., Laurent-Puig, P., Kerbrat, Ashworth, A., Orr, N., Schoemaker, M.J., Ponder, P., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., B.A., Nevanlinna, H., Brown, M.A., Milne, R.L., Arias, Perez, J.I., Menendez, P., Chenevix-Trench, G., Easton, D.F., Dunning, Muller, H., Arndt, V., Stegmaier, C., Lichtner, P., A.M.: Functional variants at the 11q13 risk locus Lochmann, M.,Justenhoven, C., Ko, Y.D., The for breast cancer regulate cyclin D1 expression GenicaNetwork, Muranen, T.A., Aittomaki, through long-range enhancers. Am J Hum Genet, K.,Blomqvist, C., Greco, D., Heikkinen, T., Ito, 92: 489-503, 2013. (PMID: 23540573) H., Iwata, H., Yatabe, Antonenkova.Y., N.N., Margolin, S., Kataja, V., Kosma, V.M., J019. Fujii, M., Toyoda, T., Nakanishi, H., Yatabe, Hartikainen, J.M., Balleine, R., kConFab Y., Sato, A., Matsudaira, Y., Ito, H., Murakami, H., Investigators, Tseng, C.C., Van Den Berg, D., Kondo, Y., Kondo, E., Hida, T., Tsujimura, T., Stram, D.O.,Neven, P., Dieudonne, A.S., Leunen, Osada, H., Sekido, Y.: TGF- synergizes with K., Rudolph, A., Nickels, S., Flesch-Janys, defects in the Hippo pathway to stimulate human D.,Peterlongo, P., Peissel, B., Bernard, L., Olson, malignant mesothelioma growth. J Exp Med, 209: J.E., Wang, X., Stevens, K., Severi, G., Baglietto, L., 479-494, 2012. (PMID: 22329991) McLean, C., Coetzee, G.A., Feng, Y., Henderson, J020. Fukatsu, A., Ishiguro, F., Tanaka, I., Kudo, B.E., Schumacher, F., Bogdanova, N.V., Labreche, T., Nakagawa, K., Shinjo, K., Kondo, Y., Fujii, M., F., Dumont, M., Yip, C.H., Mohd Taib, N.A., Hasegawa, Y., Tomizawa, K., Mitsudomi, T., Osada, Cheng, C.Y., Shrubsole, M., Long, J., Pylkas, K., H., Hata, Y., Sekido, Y.: RASSF3 downregulation Jukkola-Vuorinen, A.,Kauppila, S., Knight, J.A., increases malignant phenotypes of non-small cell Glendon, G., Mulligan, A.M., Tollennar, lung cancer. Lung Cancer, 83: 23-29, 2014. (PMID: RAEM.,Seynaeve, C.M., Kriege, M., Hooning, 24246507) M.J., van den Ouweland, A.M.W., van J021. Fukumoto, K., Taniguchi, T., Ishikawa, Y., Deurzen,C.H.M., Lu, W., Gao, Y.T., Cai, H., Kawaguchi, K., Fukui, T., Kato, K., Matsuo, K., Balasubramnian, S.P., Cross, S.S., Reed, Yokoi, K.: The utility of [18F]-fluorodeoxyglucose M.W.R.,Signorello, L., Cai, Q., Shah, M., Miao, positron emission tomography-computed H., Chan, C.W., Chia, K.S., Jakubowska, tomography in thymic epithelial tumours. Eur J A.,Jaworska, K., Durda, K., Hsiung, C.N., Wu, Cardiothorac Surg, 42: e152-156, 2012. (PMID: P.E., Yu, J.C., Ashworth, A., Jones, M.,Tessier, 23024234) D.C., Gonzalez-Neira, A., Pita, G., Alonso, M.R., Vincent, D., Bacot, F., Ambrosone, C.B., Bandera, J022. Garcia_closas, M., Cough, F., Lindstrom, S., E.V., John, E.M., Chen, G.K., Hu, J.J., Michailidou, K., Schmidt, M.K., Brook, M., Orr, Rodiquz-Gil, J.L., Bernstein, L., Press, M.F., N., Thie, S.K., Riboli, E., Feigelson, H.S., Le Ziegler, R.G., Millikan, R.M., Deming-Halverson, Marchand, L., Buring, J.E., Eccles, D., Mrion, P., S.L., Nyante, S., Ingles, S.A., Waisfisz, Q., Fasching, P.A., Bruch, H., Chang-Claude, J., Tsimikilis, H., Makalic, E., Schmidt, D., Bui, M., Carpenter, J., Godwin, A., Nevanlinna, H., Giles, Gibson, L., Muller-Myhsok, B., Hein, R., Dahmen, G.G., Cox, A., Hopper, J.L., Humphreys, M.K., N., Beckmann, L., Aaltonen, K., Czene, K., Wang, Q., Dennis, J., Dicks, E., Howat, W.J., Irwanto, A., Liu, J., Turnbull, C., FBCS, Rahman, Schoof, N., Bojesen, S.E., Lambrechts, D., Broeks, N., Meijers-Heijboer, H., Uitterlinden, A.G., A., Andrulis, I.L., Guenel, P., Burwinkel, B., Rivadeneira, F., ABCTBInvestigators Olswold, Sawyer, E.J., Hollestelle, A., Fletcher, O., Winqvist, C., Slager, S., Pilarski, R., Ademuyiwa, R., Brenner, H., Mannermaa, A., Hamann, U., F., Konstantopoulou, I., Martin, N.G., Meindl, A., Lindblom, A., Zheng, W., Devillee, P., Montgomery, G.W., Slamon, D.J., Rauh, C., Lux, Goldberg, M.S., Lubinski, Kristensene,J., V., M.P., Jud, S.M., Bruning, T., Weaver, J.E., Swerdlow, A., Anton-Culver, H., Dork, T., Muir, K., Sharma, P., Pathak, H., Tapper, W., Gerty, S., Matsuo, K., Wu, A.H., Radice, P., Teo, S.H., Shu, Durcan, L., Trichopoulos, D., Tumino, R., Peeters, X.O., Blot, W., Kang, D., Hartman, P.H., Kaaks, R., Campa,Canzian, D., F., M.,Sangrajrang, S., Shen, C.Y., Sothey, M.C., Weiderpass, E., Johansson, M., Khaw, K.T., Travis, Park, D.J., Hammet, F., Stone, J., Veer, L.J.V., R.,Clavel-Chapelon, F., Kolonel, L.N., Chen, C., Rutgers, E.J., Lophatananon, A., Stewart-Brown, Beck, A., Hankinson, S.E., Berg, C., Hoover, R.N., S., Siriwanarangsan, P.,Peto, J., Schrauder, Lissowska, J., Figueroa, J., Chasman, D.I., M.G., Ekici, A.B., Beckmann, M.W., dos Santos Gaudet, M.M., Diver, W.R., Willett, W.C., Hunter, 54

D.J., Simard, J., Benitez, J., Duning, A.M., chronic kidney disease in Japanese: Cross-Sectional Sherman, M.E., Chenevix-Trench, G., Chanock, Data from the J-MICC Study. PPAR research, 2013: S.J., Hall, P., Pharoah, P., Vachon, C., Easton, 980471, 2013. (PMID:24288525) D.F., Haiman, C.A., Kraft, P.: Genome-wide J028. Hiyoshi, M., Uemura, H., Arisawa, K., association studies identify four ER-negative Nakamoto, M., Hishida, A., Okada, R., Matsuo, K., specific breast cancer risk loci. Nat Genet, 45: Kita, Y., Niimura, H., Kuriyama, N., Nanri, H., 392-398, 2013. (PMID: 23535733) Ohnaka, K., Suzuki, S., Mikami, H., Kubo, M., J023. Goidts, V., Bageritz, J., Puccio, L., Nakata, Tanaka, H., Hamajima, N.; J-MICC Study S., Zapatka, M., Barbus, S., Toedt, G., Campos, B., Group.: Association between the Korshunov, A., Momma, S., Van, Schaftingen, E., catechol-O-methyltransferase (rs4680: Val158Met) Reifenberger, G., Herold-Mende, C., Lichter, P., polymorphism and serum alanine aminotransferase Radlwimmer, B.: RNAi screening in glioma activity. Gene, 496: 97-102, 2012. (PMID: stem-like cells identifies PFKFB4 as a key 22293393) molecule important for cancer cell survival. J029. Horinaka, M., Yoshida, T., Nakata, S., Oncogene, 31: 3235-3243, 2012. (PMID: Shiraishi, T., Tomosugi, M., Yoshikawa, S., 22056879) Wakada, M., Sakai, T.: Aclarubicin enhances tumor J024. Hara, M., Higaki, Y., Taguchi, N., Shinchi, necrosis factor-related apoptosis-inducing K., Morita, E., Naito, M., Hamajima, N., ligand-induced apoptosis through death receptor 5 Takashima, N., Suzuki, S., Nakamura, A., Ohnaka, upregulation. Cancer Sci, 103: 282-287, 2012. K., Uemura, H., Nishida, H., Hosono, S., Mikami, (PMID: 22077238) H., Kubo, M., Tanaka, H.: Effect of the PPARG2 J030. Horio, M., Sato, M., Takeyama, Y., Elshazley, Pro12Ala Polymorphism and clinical risk factors M., Yamashita, R., Hase, T., Yoshida, K., Usami, for diabetes mellitus on HbA1c in the Japanese N., Yokoi, K., Sekido, Y., Kondo, M., Toyokuni, S., general population. J Epidemiol, 22: 523-531, 2012. Gazdar, A.F., Minna, J.D., Hasegawa, Y.: Transient (PMID: 23006958) but not stable ZEB1 knockdown dramatically J025. Hishida, A., Morita, E., Naito, M., Okada, R., inhibits growth of malignant pleural mesothelioma Wakai, K., Matsuo, K., Nakamura, K., Takashima, cells. Ann Surg Oncol, Suppl 3:S634-45, 2012. N., Suzuki, S., Takezaki, T., Mikami, H., Ohnaka, (PMID: 22086445) K., Watanabe, Y., Uemura, H., Kubo, M., Tanaka, J031. Hosono, S., Matsuo, K., Ito, H., Oze, I., H., Hamajima, N.: Associations of apolipoprotein Hirose, K., Watanabe, M., Nakanishi, T., Tajima, A5 (APOA5), glucokinase (GCK) and glucokinase K., Tanaka, H.: Polymorphisms in base excision regulatory protein (GCKR) polymorphisms and repair genes are associated with endometrial cancer lifestyle factors with the risk of dyslipidemia and risk among postmenopausal Japanese women. Int J dysglycemia in Japanese - a cross-sectional data Gynecol Cancer, 23: 1561-1568, 2013. (PMID: from the J-MICC Study. Endocr J, 59: 589-599, 24172093) 2012. (PMID: 22517333) J032. Hosono, S., Matsuo, K., Ito, H., Watanabe, J026. Hishida, A., Okada, R., Naito, M., Morita, E., M., Hirose, K., Nakanishi, T., Tajima, K., Tanaka, Wakai, K., Hamajima, N., Hosono, S., Nanri, H., H.: Interaction between CYP19A1 polymorphisms Turin, T.C., Suzuki, S., Kuwabara, K., Mikami, H., and body mass index in the risk of endometrial Budhathoki, S., Watanabe, I., Arisawa, K., Kubo, cancer in postmenopausal Japanese women. Asian M., Tanaka, H.: Polymorphisms in genes encoding Pac J Cancer Prev, 12: 2747-2752, 2012. (PMID: antioxidant enzymes(SOD2, CAT,GPx, TXNRD, 22320986) SEPP1, SEP15 and SELS) and risk of chronic kidney diseasein Japanese - cross-sectional data J033. Ikawa, K., Satou, A., Fukuhara, M., from the J-MICC study. J Clin Biochem Nutr, 53: Matsumura, S., Sugiyama, N., Goto, H., Fukuda, 15-20, 2013. (PMID: 23874065) M., Inagaki, M., Ishihama, Y., Toyoshima, F.: Inhibition of endocytic vesicle fusion by J027. Hishida, A., Wakai, K., Naito, M., Tamura, T., Plk1-mediated phosphorylation of vimentin during Kawai, S., Hamajima, N., Oze, I., Imaizumi, T., mitosis. Cell Cycle, 131: 126-137, 2014. (PMID: Turin, TC., Suzuki, S., Kheradmand, M., Mikami, 24196446) H., Ohnaka, K., Watanabe, Y., Arisawa, K., Kubo, M., Tanaka, H. Polymorphisms in PPAR genes J034. Ikeda, M., Aleksic, B., Yamada, K., Iwayama, (PPARD, PPARG, and PPARGC1A) and the risk of Y., Matsuo, K., Numata, S., Watanabe, Y., Ohnuma, T., Kaneko, T., Fukuo, Y., Okochi, T., Toyota, T., 55

Hattori, E., Shimodera, S., Itakura, M., HER2-overexpressing, and triple-negative breast Nunokawa, A., Shibata, N., Tanaka, H., Yoneda, cancer in Japanese women. Ann Oncol, H., Arai, H., Someya, T., Ohmori, T., Yoshikawa, T., 23: 2435-2441, 2012. (PMID: 22328736) Ozaki, N., Iwata, N.: Genetic evidence for J042. Itatani, Y., Kawada, K., Fujishita, T., association between NOTCH4 and schizophrenia Kakizaki, F., Hirai, H., Matsumoto, T., Iwamoto, supported by a GWAS follow-u study in a Japanese M., Inamoto, S., Hatano, E., Hasegawa, S., popultion. Mol Psychiatry, 18: 636-638, 2013. Maekawa, T., Uemoto, S., Sakai, Y., Taketo, M.M.: (PMID:: 22641179) Loss of SMAD4 from colorectal cancer cells J035. Imataki, O., Ansén, S., Tanaka, M., Butler, promotes CCL15 expression to recruit CCR1+ M.O., Berezovskaya, A., Milstein, M.I., Kuzushima, myeloid cells and facilitate liver metastasis. K., Nadler, L.M., Hirano, N.: IL-21 can Gastroenterology, 145: 1064-1075, 2013. (PMID: supplement suboptimal Lck-independent MAPK 23891973) activation in a STAT-3-dependent manner in human J043. Ito, H., Gallus, S., Hosono, S., Oze, I., CD8+ T cells. J Immunol, 188: 1609-1619, 2012. Fukumoto, K., Yatabe, Y., Hida, T., Mitsudomi, T., (PMID: 22238455) Negri, E., Yokoi, K., Tajima, K., La Vecchia, C., J036. Inoko, A., Matsuyama, M., Goto, H., Tanaka, H., Matsuo, K.: Time to first cigarette and Ohmuro-Matsuyama, Y., Hayashi, Y., Enomoto, lung cancer risk in Japan. Ann Oncol, 24: M., Ibi, M., Urano, T., Yonemura, S., Kiyono, T., 2870-2875, 2013. (PMID: 24013511) Izawa, I., Inagaki, M.: Trichoplein and Aurora A J044. Ito, H., McKay, J.D., Hosono, S., Hida, T., block aberrant primary cilia assembly in Yatabe, Y., Mitsudomi, T., Brennan, P., Tanaka, H., proliferating cells. J Cell Biol, 197: 391-405, 2012. Matsuo, K.: Association between a genome-wide (PMID: 22529102) association study-identified locus and the risk of J037. Inoue, M., Nagata, C., Tsuji, I., Sugawara, lung cancer in Japanese population. J Thorac Oncol, Y., Wakai, K., Tamakoshi, A., Matsuo, K., Mizoue, 7: 790-798, 2012. (PMID: 22430809) T., Tanaka, K., Ssazuki, S., Tsugane, S.: Impact of J045. Iwanaga, M., Chiang, C.J., Soda, M., Lai, alcohol intake on total mortality and mortality from M.S., Yang, Y.W., Miyazaki, Y., Matsuo, K., major causes in Japanese: A pooled analysis of 6 Matsuda, T., Sobue, T.: Incidence of large-scale cohort studies in Japan. J Epidemiol lymphoplasmacytic Commun H, 66: 448-456, 2012. (PMID: 21148820) lymphoma/Waldenstrm'smacroglobulinaemia in J038. Ishiguro, F., Murakami, H., Mizuno, T., Japan and Taiwan population-based cancer Fujii, M., Kondo, Y., Usami, N., Taniguchi, T., registries, 1996-2003. Int J Cancer, 134: 174-180, Yokoi, K., Osada, H., Sekido, Y.: Membranous 2013. (PMID: 23784625) expression of activated leukocyte cell adhesion J046. Jeong, H.J., Ohmuro-Matsuyama, Y., molecule (ALCAM) contributes to poor prognosis Ohashi, H., Ohsawa, F., Tatsu, Y., Inagaki, M., and malignant phenotypes of non-small cell lung Ueda, H.: Detection of vimentin serine cancer. J Surg Res, 179: 24-32, 2013. (PMID: phosphorylation by multicolor Quenchbodies. 22985775) Biosens Bioelectron, 40: 17-23, 2013. (PMID: J039. Ishiguro, F., Murakami, H., Mizuno, T., 22795529) Fujii, M., Kondo, Y., Usami, N., Yokoi, K., Osada, J047. Jia, W.H., Zhang, B., Matsuo, K., Shin, A., H., Sekido, Y.: Activated leukocyte cell adhesion Xiang, Y.B., Jee, S.H., Kim, D.H., Ren, Z., Caii, Q., molecule (ALCAM) promotes malignant Long, J., Shi, J., Wen, W., Yang, G., Delahnty, R.J., phenotypes of malignant mesothelioma. J Thorac GECCO and CCFR, Ji, B.T., Pan, Z.Z., Matsuda, Oncol, 7: 890-899, 2012. (PMID: 22722789) F., Gao, Y.T., Oh, J.H., Ahn, Y.O., Park, E.J., Li, J040. Islam, T., Ito, H., Sueta, A., Hosono, S., H.L., Park, J.W., Jo, J., Jeong, J.Y., Hosono, S., Hirose, K., Watanabe, M., Iwata, H., Tajima, K., Casey, G., Peteres, U., Shu, X.O., Zeng, Y.X., Tanaka, H., Matsuo, K.: Alcohol and dietary folate Zheng, W.: Genome-wide association analyses in intake andrisk of breast cancer: a case -control East Asians identify new susceptibility loci for study in Japan. Eur J Cancer, 22: 358-366, 2013. colorectal cancer. Nat Genet, 45: 191-196, 2013. (PMID: 23183091) (PMID: 23263487) J041. Islam, T., Matsuo, K., Ito, H., Hosono, S., J048. Kanda, T., Horikoshi, N., Murata, T., Watanabe, M., Iwata, H., Tajima, K., Tanaka, H.: Kawashima, D., Sugimoto, A., Narita, Y., Reproductive and hormonal risk factors for luminal, Kurumizaka, H., Tsurumi, T.: Interaction between 56 basic residues of Epstein-Barr virus EBNA1 protein Y.: Clinical value of flow cytometric and cellular chromatin mediates viral plasmid immunophenotypic analysis for minimal residual maintenance. J Biol Chem, 288: 24189-24199, 2013. disease detection in autologous stem-cell products (PMID: 23836915) of follicular and mantle cell lymphomas. Leukemia, 26: 166-169, 2012 (PMID: 21818114) J049. Kanda, T., Ochi, T., Fujiwara, H., Yasukawa, M., Okamoto, S., Mineno, J., Kuzushima, K., J056. Kawaguchi, T., Sumida, Y., Umemura, A., Tsurumi, T.: HLA-restricted presentation of WT1 Matsuo, K., Takahashi, M., Takamura, T., Yasui, tumor antigen in B-lymphoblastoid cell lines K., Saibara, T., Hashimoto, E., Kawanaka, M., established using a maxi-EBV system. Cancer Gene Watanabe, S., Kawata, S., Imai, Y., Kokubo, M., Ther, 19: 566-571, 2012. (PMID: 22722376) Shima, T., Park, H., Tanaka, H., Tajima, K., Yamada, R., Matsuda, F., Okanoue, T.: Genetic J050. Kane, E., Roman, E., Becker, N., Bernstein, polymorphisms of the human PNPLA3 gene are L., Boffetta, P., Bracci, P., Cerhan, J.R., Chiu, B., strongly associated with severity of non-alcoholic Cocco, P., Costas, L., Foretova, L., La, Vecchia, C., fatty liver disease in Japanese. Plos One, 7: e38322, Matsuo, K., Maynadie, M., Sanjose, S., Spinelli, 2012. (PMID: 22719876) J.J., Staines, A., Talamini, R., Wang, S.S., Zhang, Y., Zheng, T., Kricker, A.: Menstrual and J057. Kawakita, D., Hosono, S., Ito, H., Oze, I., reproductive factors, and hormonal contraception Watanabe, M., Hanai, N., Hasegawa, Y., Tajima, use: associations with non-Hodgkin lymphoma in a K., Murakami, S., Tanaka, H., Matsuo, K.: Impact pooled analysis of InterLymph case-control studies. of smoking status on clinical outcome in oral cavity Ann Oncol, 23: 2362-2374, 2012. (PMID: cancer patients. Oral Oncol, 48: 186-191, 2012. 22786757) (PMID: 21996543) J051. Kane, E.V., Bernstein, L., Bracci, P.M., J058. Kawakita, D., Matsuo, K., Sato, F., Oze, I., Cerhan, J.R., Costas, L., Dal, Maso. L., Holly, Hosono, S., Ito, H., Watanabe, M., Yatabe, Y., E.A., La, Vecchia, C., Matsuo, K., Sanjose, S., Hanai, N., Hasegawa, Y., Tajima, K., Murakami, Spinelli, J.J., Wang, S.S., Zhang, Y., Zheng, T., S., Tanaka, H.: Association between dietary folate Roman, E., Kricker, A.; for the InterLymph intake and clinical outcome in head and neck Consortium.: Postmenopausal hormone therapy and squamous cell carcinoma. Ann Oncol, 23: 186-192, non-Hodgkin lymphoma: a pooled analysis of 2012. (PMID: 21460376) InterLymph case-control studies. Ann Oncol, 24: J059. Kawakita, D., Sato, F., Hosono, S., Ito, H., 433-441, 2013. (PMID: 22967995) Oze, I., Watanabe, M., Hanai, N., Hatooka, S., J052. Karube, K., Tsuzuki, S., Yoshida, N., Arita, Hasegawa, Y., Shinoda, M., Tajima, K., Murakami, K., Kato, H., Katayama, M., Ko, Y-H., Ohshima, K., S., Tanaka, H., Matsuo, K.: Inverse association Nakamura, S., Kinoshita, T., Seto, M.: between yoghurt intake and upper aerodigestive Comprehensive gene expression profiles of NK cell tract cancer risk in a Japanese population. Eur J neoplasms identify vorinostat as an effective drug Cancer Prev, 21: 453-459, 2012 . (PMID: candidate. Cancer Lett, 333: 47-55, 2013. (PMID: 22179690) 23348693) J060. Kawashima, D., Kanda, T., Murata, T., Saito, J053. Karube, K., Tsuzuki, S., Yoshida, N., Arita, S., Sugimoto, A., Narita, Y., Tsurumi, T.: Nuclear K., Liu, F., Kondo, E., Ko, Y.H., Ohshima, K., transport of Epstein-Barr virus DNA polymerase is Nakamura, S., Kinoshita, T., Seto, M.: dependent on the BMRF1 polymerase processivity Lineage-specific growth inhibition of NK cell lines factor and molecular chaperone Hsp90. J Virol, 87: by FOXO3 in association with Akt activation status. 6482-6491, 2013. (PMID: 23552409) Exp Hematol, 40: 1005-1015.e6, 2012. (PMID: J061. Kim, H.C., Lee, J.Y., Sung, H., Choi, J.Y., 22922206) Park, S.K., Lee, K.M., Kim, Y.J., Go, M.J., Li, L., J054. Kasahara, K., Goto, H., Izawa, I., Kiyono, T., Cho, Y.S., Park, M., Kim, D.J., Oh, J.H., Kim, Watanabe, N., Elowe, S., Nigg, E.A., Inagaki, M.: J.W., Jeon, J.P., Jeon, S.Y., Min, H., Kim, H.M., PI 3-kinase-dependent phosphorylation of Park, J., Yoo, K.Y., Noh, D.Y., Ahn, S.H., Lee, Plk1-Ser99 promotes association with 14-3-3γ and M.H., Kim, S.W., Lee, J.W., Park, B.W., Park, W.Y., is required for metaphase-anaphase transition. Nat Kim, E.H., Kim, M.K., Han, W., Lee, S.A., Matsuo, Commun, 4: 1882, 2013. (PMID: 23695676) K., Shen, C.Y., Wu, P.E., Hsiung, C.N., Lee, J.Y., Kim, H.L., Han, B.G., Kang, D.: A genome-wide J055. Kato, H., Yamamoto, K., Oki, Y., Ine, S., Taji, association study identifies a breast cancer risk H., Chihara, D., Kagami, Y., Seto, M., Morishima, 57 variant in ERBB4 at 2q34: results from the Seoul analysis identifies new lung cancer susceptibility Breast Cancer Study. Breast Cancer Res, 14: R56, loci in never-smoking women in Asia. Nat Genet, 2012. (PMID: 22452962) 44: 1330-1335, 2012. (PMID: 23143601) J062. Kimura, H., Karube, K., Ito, Y., Hirano, K., J066. Li, L., Choi, J.Y., Lee, K.M., Sung, H., Park, Suzuki, M., Iwata, S., Seto, M.: Rare occurrence of S.K., Oze, I., Pan, K.F., You, W.C., Chen, Y.X., JAK3 mutations in natural killer cell neoplasms in Fang, J.Y., Matsuo, K., Kim, W.H., Yuasa, Y., Japan. Leuk Lymphoma, 2013. [Epub ahead of Kang, D.: DNA methylation in peripheral blood: a print] (PMID: 23808814) potential biomarker for cancer molecular epidemiology. J Epidemiol, 22: 384-394, 2012. J063. Kondo, E., Saito, K., Tashiro, Y., Kamide, K., (PMID: 22863985) Uno, S., Furuya, T., Mashita, M., Nakajima, K., Tsumuraya, T., Kobayashi, N., Nishibori, M., J067. Li, P., Goto, H., Kasahara, K., Matsuyama, Tanimoto, M., Matsushita, M.: Tumour M., Wang, Z., Yatabe, Y., Kiyono, T., Inagaki, M.: lineage-homing cell-penetrating peptides as P90 RSK arranges Chk1 in the nucleus for anticancer molecular delivery systems. Nat monitoring of genomic integrity during cell Commun, 3: 951-963, 2012. (PMID: 22805558) proliferation. Mol Biol Cell, 23: 1582-1592, 2012. (PMID: 22357623) J064. Kondo, S., Demachi-Okamura, A., Hirosawa, T., Maki, H., Fujita, M., Uemura, Y., Akatsuka, Y., J068. Lin, Y., Fu, R., Grant, E., Chen, Y., Lee, J.E., Yamamoto, E., Shibata, K., Ino, K., Kikkawa, F., Gupta, P.C., Ramadas, K., Inoue, M., Tsugane, S., Kuzushima, K.: An HLA-modified ovarian cancer Gao, Y.T., Tamakoshi, A., Shu, X.O., Ozasa, K., cell line induced CTL responses specific to an Tsuji, I., Kakizaki, M., Tanaka, H., Chen, C.J., Yoo, epitope derived from claudin-1 presented by K.Y., Ahn, Y.O., Ahsan, H., Pendnekar, M.S., HLA-A*24:02 molecules. Hum Immunol, 74: Saubaget, C., Sasazuki, S., Yang, G., Xiang, Y.B., 1103-1110, 2013. (PMID: 23806269) Ohishi, W., Watanabe, T., Nishino, Y., Matsuo, K., You, S.L., Park, S.K., Kim, D.H., Parbez, F., J065. Lan, Q., Hsiung, C.A., Matsuo, K., Hong, Rolland, B., McLearan, D., Sinha, R., Boffetta, P., Y.C., Seow, A., Wang, Z., Hosgood, H.D. 3rd, Zheng, W., Thomquist, M., Feng, Z., Kang, D., Chen, K., Wang, J.C., Chatterjee, N., Hu, W., Potter, J.D.: Association of body mass index and Wong, M.P., Zheng, W., Caporaso, N., Park, J.Y., risk of death from pancreas cancer in Asians: Chen, C.J., Kim, Y.H., Kim, Y.T., Landi, M.T., findings from the Asia Cohort Consortium. Eur J Shen, H., Lawrence, C., Burdett, L., Yeager, M., Cancer Prev, 22: 244-250, 2013. (PMID: 23044748) Yuenger, J., Jacobs, K.B., Chang, I.S., Mitsudomi, T., Kim, H.N., Chang, G.C., Bassig, B.A., Tucker, J069. Liu, F., Asano, N., Tatematsu, A., Oyama, T., M., Wei, F., Yin, Z., Wu, C., An, S.J., Qian, B., Lee, Kitamura, K., Suzuki, K., Yamamoto, K., V.H., Lu, D., Liu, J., Jeon, H.S., Hsiao, C.F., Sung, Sakamoto, N., Taniwaki, M., Kinoshita, T., J.S., Kim, J.H., Gao, Y.T., Tsai, Y.H., Jung, Y.J., Nakamura, S.: Plasmablastic lymphoma of the Guo, H., Hu, Z., Hutchinson, A., Wang, W.C., elderly: a clinicopathological comparison with Klein, R., Chung, C.C., Oh, I.J., Chen, K.Y., age-related Epstein-Barr virus-associated B cell Berndt, S.I., He, X., Wu, W., Chang, J., Zhang, lymphoproliferative disorder. Histopathology, 61: X.C., Huang, M.S., Zheng, H., Wang, J., Zhao, X., 1183-1197, 2012, (PMID: 22958176) Li, Y., Choi, J.E., Su, W.C., Park, K.H., Sung, S.W., J070. Liu, F., Karube, K., Kato, H., Arita, K., Shu, X.O., Chen, Y.M., Liu, L., Kang, C.H., Hu, L., Yoshida, N., Yamamoto, K., Tsuzuki, S., Kim, W., Chen, C.H., Pao, W., Kim, Y.C., Yang, T.Y., Xu, J., Ko, Y-H., Seto, M.: Mutation analysis of NF-κB Guan, P., Tan, W., Su, J., Wang, C.L., Li, H., Sihoe, signal pathway-related genes in ocular MALT A.D., Zhao, Z., Chen, Y., Choi, Y.Y., Hung, J.Y., lymphoma. Int J Clin Exp, 5: 436-441, 2012. Kim, J.S., Yoon, H.I., Cai, Q., Lin, C.C., Park, I.K., (PMID: 22808296) Xu, P., Dong, J., Kim, C., He, Q., Perng, R.P., Kohno, T., Kweon, S.S., Chen, C.Y., Vermeulen, R., J071. Liu, F., Yoshida, N., Suguro, M., Kato, H., Wu, J., Lim, W.Y., Chen, K.C., Chow, W.H., Ji, Karube, K., Arita, K., Yamamoto, K., Tsuzuki, S., B.T., Chan, J.K., Chu, M., Li, Y.J., Yokota, J., Li, Oshima, K., Seto, M.: Clonal heterogeneity of J., Chen, H., Xiang, Y.B., Yu, C.J., Kunitoh, H., mantle cell lymphoma revealed by array Wu, G., Jin, L., Lo, Y.L., Shiraishi, K., Chen, Y.H., comparative genomic hybridization. Eur J Lin, H.C., Wu, T., Wu, Y.L., Yang, P.C., Zhou, B., Haematol, 90: 51-58, 2013. (PMID: 23110670) Shin, M.H., Fraumeni, J.F. Jr, Lin, D., Chanock, J072. Ma, J., Xiao, F., Xiong, M., Andrew, A.S., S.J., Rothman, N.: Genome-wide association Brenner, H., Duell, E.J., Haugen, A., Hoggart, C., 58

Hung, R.J., Lazarus, P., Liu, C., Matsuo, K., risk of stomach cancer. Carcinogenesis, 34: Mayordomo, J.I., Schwartz, A.G., Staratschek-Jox, 1510-1515, 2013. (PMID: 23455379) A., Wichmann, E., Yang, P., Amos, C.I.: Natural J079. Matsuo, K., Rossi, M., Negri, E., Oze, I., and orthogonal interaction framework for modeling Hosono, S., Ito, H., Watanabe, M., Yatabe, Y., gene-environment interactions with application to Hasegawa, Y., Tanaka, H., Tajima, K., La, Vecchia, lung cancer. Hum Hered, 73: 185-194, 2012. C.: Folate, alcohol, and aldehyde dehydrogenase 2 (PMID: 22889990) polymorphism and the risk of oral and pharyngeal J073. Ma, X., Beeghly-Fadiel, A., Lu, W., Shi, J., cancer in Japanese. Eur J Cancer Prev, 21: 193-198, Xiang, Y.B., Cai, Q., Shen, H., Shen, C.Y., Ren, Z., 2012. (PMID: 21946912) Matsuo, K., Khoo, U.S., Iwasaki, M., Long, J., J080. Matsuyama, M., Tanaka, Hir., Inoko, A., Zhang, B., Ji, B.T., Zheng, Y., Wang, W., Hu, Z., Goto, H., Yonemura, S., Kobori, K., Hayashi, Y., Liu, Y., Wu, P.E., Shieh, Y.L., Wang, S., Xie, X., Ito, Kondo, E., Itohara, S., Izawa, I., Inagaki, M.: H., Kasuga, Y., Chan, K.Y., Iwata, H., Tsugane, S., Defect of mitotic vimentin phosphorylation causes Gao, Y.T., Shu, X.O., Moses, H.L., Zheng, W.: microophthalmia and cataract via aneuploidy and Pathway analyses identify TGFBR2 as potential senescence in lens epithelial cells. J Biol Chem, breast cancer susceptibility gene: results from a 288: 35626-35635, 2013. (PMID: 24142690) consortium study among Asians. Cancer Epidemiol Biomarkers Prev, 21: 1176-1184, 2012. (PMID: J081. Matsuzuka, T., Takahashi, K., Kawakita, D., 22539603) Kohono, N., Nagafuji, H., Yamauchi, K., Suzuki, M., Miura, T., Furuya, N., Yatabe, Y., Matsuo, K., J074. Maeda, O., Shibata, K., Hosono, S., Omori, K., Hasegawa, Y.: Intraoperative molecular Fujiwara, S., Kajiyama, H., Ino, K., Nawa, A., assessment for lymph node metastasis in head and Tamakoshi, K., Kikkawa, F.: Spectrin αII and βII neck squamous cell carcinoma using one-step tetramers contribute to platinum anticancer drug nucleic acid amplification (OSNA) assay. Ann Surg resistance in ovarian serous adenocarcinoma. Int J Oncol, 19: 3865-3870, 2012. (PMID: 22618721) Cancer, 130: 113-121, 2012. (PMID: 21328338) J082. Michailidou, K., Hall, P., Gonzalez-Neira, A., J075. Maseki, S., Ijichi, K., Tanaka, H., Fujii, M., Ghoussaini, M., Dennis, J., Milne, R.L., Schmidt, Hasegawa, Y., Ogawa, T., Murakami, S., Kondo, M.K., Chang-Claude, J., Bojesen, S.E., Bolla, E., Nakanishi, H.: Acquisition of EMT phenotype M.K., Wang, Q., Dicks, E., Lee, A., Turnbull, C., in the gefitinib-resistant cells of a head and neck Rahman, N.; Breast and Ovarian Cancer squamous cell carcinoma cell line through Susceptibility Collaboration, Fletcher, O., Peto, J., Akt/GSK-3β/snail signaling pathway. Brit J Cancer, Gibson, L., Dos, Santos, Silva, I., Nevanlinna, H., 106: 1196-1120, 2012. (PMID: 22315058) Muranen, T.A., Aittomki, K., Blomqvist, C., Czene, J076. Matsuo, K., Gallus, S., Negri, E., Kawakita, K., Irwanto, A., Liu, J., Waisfisz, Q., D., Oze, I., Hosono, S., Ito, H., Hatooka, S., Meijers-Heijboer,H., Adank, M.; Hereditary Hasegawa, Y., Shinoda, M., Tajima, K., Vecchia, Breast and Ovarian Cancer Research Group C.L., Tanaka, H.: Time to first cigarette and upper Netherlands (HEBON), van der Luijt, R.B., Hein, aerodigestive tract cancer risk in Japan. Cancer R., Dahmen, N., Beckman, L., Meindl, A., Epidemiol Biomarkers Prev, 21: 1186-1192, 2012. Schmutzler, R.K., Miller-Myhsok, B., Lichtner, P., (PMID: 22971902) Hopper, J..L, Southey, M.C., Makalic, E., Schmidt, D.F., Uitterlinden, A.G., Hofman, A., Hunter, D.J., J077. Matsuo, K., Mizoue, T., Tanaka, K., Tsuji, I., Chanock, S.J., Vincent, D., Bacot, F., Tessier, D.C., Sugawara, Y., Sasazuki, S., Nagata, C., Tamakoshi, Canisius, S., Wessels, L.F., Haiman, C.A., Shah, A., Wakai, K., Inoue, M., Tsugane, S.: Association M., Luben, R., Brown, J., Luccarini, C., Schoof, between body mass index and the colorectal cancer N., Humphreys, K., Li, J., Nordestgaard, B.G., risk in Japan: pooled analysis of population-based Nielsen, S.F., Flyger, H., Couch, F.J., Wang, X., cohort studies in Japan. Ann Oncol, 23: 479-190, Vachon, C., Stevens, K.N., Lambrechts, D., Moisse, 2012. (PMID: 21597097) M., Paridaens, R., Christiaens, M.R., Rudolph, A., J078. Matsuo, K., Oze, I., Hosono, S., Ito, H., Nickels, S., Flesch-Janys, D., Johnson, N., Aitken, Watanabe, M., Ishioka, K., Ito, S., Tajika, M., Z., Aaltonen, K., Heikkinen, T., Broeks, A., Veer, Yatabe, Y., Niwa, Y., Yamao, K., Nakamura, S., L.J., van der Schoot, C.E., Gunel, P., Truong, T., Tajima, K., Tanaka, H.: The aldehyde Laurent-Puig, P., Menegaux, F., Marme, F., dehydrogenase 2 (ALDH2) Glu504Lys Schneeweiss, A., Sohn, C., Burwinkel, B., Zamora, polymorphism interacts with alcohol drinking in the M.P., Perez, J.I., Pita, G., Alonso, M.R., Cox, A., 59

Brock, I.W., Cross, S.S., Reed, M.W., Sawyer, E.J., by upregulating transcription of cell cycle Tomlinson, I., Kerin, M.J., Miller, N., Henderson, promoting genes. Oncogene, 31: 5117-5122, 2012. B.E., Schumacher, F., Le, Marchand, L., Andrulis, (PMID: 22286761) I.L., Knight, J.A., Glendon, G., Mulligan, A.M; J085. Murakami, H., Ito, S., Tanaka, H., Kondo, kConFab Investigators; stralian Ovarian Cancer E., Kodera, Y., Nakanishi, H.: Establishment of Study Group, Lindblom, A., Margolin, S., Hooning, New intraperitoneal paclitaxel-resistant gastric M.J., Hollestelle, A., van den Ouweland, A.M., cancer cell lines and comprehensive gene Jager, A., Bui, Q.M., Stone, J., Dite, G.S., Apicella, expression analysis. Anticancer Res, 33: 4299-4307, C., Tsimiklis, H., Giles, G.G., Severi, G., Baglietto, 2013. (PMID: 24122996) L., Fasching, P.A., Haeberle, L., Ekici, A.B., Beckmann, M.W., Brenner, H., Miller, H., Arndt, J086. Murakami, H., Nakanishi, H., Tanaka, H., V., Stegmaier, C., Swerdlow, A., Ashworth, A., Orr, Ito, S., Misawa, K., Ito, Y., Ikehara, Y., Kondo, E., N., Jones, M., Figueroa, J., Lissowska, J., Brinton, Kodera, Y.: Establishment and characterization of L., Goldberg, M.S., Labrche, F., Dumont, M., novel gastric signet-ring cell and non signet-ring Winqvist, R., Pylks, K., Jukkola-Vuorinen, A., cell, poorly-differentiated adenocarcinoma cell lines Grip, M., Brauch, H., Hamann, U., Brning, T; with low and high malignant potential. Gastric GENICA (Gene Environment Interaction and Cancer, 16: 74-83, 2013. (PMID: 22450770) Breast Cancer in Germany) Network, Radice, P., J087. Murata, T., Iwata, S., Siddiquey, M.N., Peterlongo, P., Manoukian, S., Bonanni, B., Kanazawa, T., Goshima, F., Kawashima, D., Devilee, P., Tollenaar, R.A., Seynaeve, C., van Kimura, H., Tsurumi, T.: Heat shock protein 90 Asperen, C.J., Jakubowska, A., Lubinski, J., inhibitors represslatent membrane protein 1 (LMP1) Jaworska, K., Durda, K., Mannermaa, A., Kataja, expression and proliferation of Epstein-Barr V., Kosma, V.M., Hartikainen, J.M., Bogdanova, virus-positive natural killer cell lymphoma. PLoS N.V., Antonenkova, N.N., Drk, T., Kristensen, V.N., One, 8: e63566, 2013. (PMID: 23658841) Anton-Culver, H., Slager, S., Toland, A.E., Edge, S., Fostira, F., Kang, D., Yoo, K.Y., Noh, D.Y., J088. Murata, T., Kondo, Y., Sugimoto, A., Matsuo, K., Ito, H., Iwata, H., Sueta, A., Wu, A.H., Kawashima, D., Saito, S., Isomura, H., Kanda, T., Tseng, C.C., Van Den, Berg. D., Stram, D.O., Shu, Tsurumi, T.: Epigenetic histone modification of X.O., Lu, W., Gao, Y.T., Cai, H., Teo, S.H., Yip, Epstein-Barr virus BZLF1 promoter during latency C.H., Phuah, S.Y., Cornes, B.K., Hartman, M., and reactivation in Raji cells. J Virol, 86: Miao, H., Lim, W.Y., Sng, J.H., Muir, K., 4752-4761, 2012. (PMID: 22357272) Lophatananon, A., Stewart-Brown, S., J089. Murata, T., Narita, Y., Sugimoto, A., Siriwanarangsan, P., Shen, C.Y., Hsiung, C.N., Kawashima, D., Kanda, T., Tsurumi, T.: Wu, P.E., Ding, S.L., Sangrajrang, S., Gaborieau, Contribution of myocyte enhancer factor 2 (MEF2) V., Brennan, P., McKay, J., Blot, W.J., Signorello, family transcription factors to BZLF1 expression in L.B., Cai, Q., Zheng, W., Deming-Halverson, S., Epstein-Barr virus reactivation from latency. J Virol, Shrubsole, M., Long, J., Simard, J., Garcia-Closas, 87: 10148-10162, 2013. (PMID: 23843637) M., Pharoah, P.D., Chenevix-Trench, G., Dunning, A.M., Benitez, J., Easton, D.F.: Large-scale J090. Nagai, K., Ochi, T., Fujiwara, H., An, J., genotyping identifies 41 novel breast cancer Shirakata, T., Mineno, J., Kuzushima, K., Shiku, susceptibility loci. Nat Genet, 45: 353-361, 2013. H., Melenhorst, J.J., Gostick, E., Price, D.A., Ishii, (PMID: 23535759) E., Yasukawa, M.: Aurora kinase A-specific T-cell receptor gene transfer redirects T lymphocytes to J083. Miyazaki, Y., Fujiwara, H., Asai, H., Ochi, F., display effective antileukemia reactivity. Blood, Ochi, T., Azuma, T., Ishida, T., Okamoto, S., 119: 368-376, 2012. (PMID: 220255259) Mineno, J., Kuzushima, K., Shiku, H., Yasukawa, M.: Development of a novel redirected T-cell-based J091. Nagata, C., Mizoue, T., Tanaka, K., Tsuji, I., adoptive immunotherapy targeting human Tamakoshi, A., Wakai, K., Matsuo, K., Ito, H., telomerase reverse transcriptase for adult T-cell Sasazuki, S., Inoue, M., Tsugane, S.; for the leukemia. Blood, 121: 4894-4901, 2013. (PMID: Research Group for the Development and 23641014) Evaluation of Cancer Prevention Strategies in Japan.: Breastfeeding and breast cancer risk: an J084. Mizuno, T., Murakami, H., Fujii, M., evaluation based on a systematic review of Ishiguro, F., Tanaka, I., Kondo, Y., Akatsuka, S., epidemiologic evidence among the Japanese Toyokuni, S., Yokoi, K., Osada, H., Sekido, Y.: YAP population. Jpn J Clin Oncol, 42: 124-130, 2012. induces malignant mesothelioma cell proliferation (PMID: 22210922) 60

J092. Nakagawa, T., Takeuchi, S., Yamada, T., accumulation of p21WAF1/CIP1. Cell Death Dis, 4: Nanjo, S., Ishikawa D, Sano, T., Kita, K., e859, 2013. (PMID: 24136223) Nakamura, T., Matsumoto, K., Suda, K., J099. Nishimura, T., Kaneko, S., Mitsudomi, T., Sekido, Y., Uenaka, T., Yano, S.: Kawana-Tachikawa, A., Tajima, Y., Goto, H., Zhu, Combined therapy with mutant-selective EGFR D., Nakayama-Hosoya, K., Iriguchi, S., Uemura, inhibitor and Met kinase inhibitor to overcome Y., Shimizu, T., Takayama, N., Yamada, D., erlotinib resistance in EGFR mutant lung cancer. Nishimura, K., Ohtaka, M., Watanabe, N., Mol Cancer Ther, 11: 2149-2157, 2012. (PMID: Takahashi, S., Iwamoto, A., Koseki, H., Nakanishi, 22844075) M., Eto, K., Nakauchi, H.: Generation of J093. Nakao, M., Hosono, S., Ito, H., Oze, I., rejuvenated antigen-specific T cells by Watanabe, M., Mizuno, N., Yatabe, Y., Yamao, K., reprogramming to pluripotency and Niimi, A., Tajima, K., Tanaka, H., Matsuo, K.: redifferentiation. Cell Stem Cell, 12: 114-126, 2013. Cigarette smoking and pancreatic cancer risk: a (PMID: 23290140) revisit with an assessment of the nicotine J100. Nishio, N., Fujita, M., Tanaka, Y., Maki, H., dependence phenotype. Asian Pac J Cancer Prev, Zhang, R., Hirosawa, T., Demachi-Okamura, A., 14: 4409-4413, 2013. (PMID: 23992012) Uemura, Y., Taguchi, O., Takahashi, Y., Kojima, S., J094. Nakao, M., Hosono, S., Ito, H., Watanabe, Kuzushima, K.: Zoledronate sensitizes M., Mizuno, N., Sato, S., Yatabe, Y., Yamao, K., neuroblastoma-derived tumor-initiating cells to Ueda, R., Tajima, K., Tanaka, H., Matsuo, K.: cytolysis mediated by human γδ T cells. J Selected polymorphisms of base excision repair Immunother, 35: 598-606, 2012. (PMID: 22996365 genes and pancreatic cancer risk in Japanese. J J101. Nishiyama, T., Kishino, H., Suzuki, S., Ando, Epidemiol, 22: 477-483, 2012. (PMID: 22850545) R., Niimura, H., Uemura, H., Horita, M., Ohnaka, J095. Nakata, I., Yamashiro, K., Akagi-Kurashige, K., Kuriyama, N., Mikami, H., Takashima, N., Y., Miyake, M., Kumagai, K., Tsujikawa, A., Liu, Mastuo, K., Guang, Y., Wakai, K., Hamajima, N., K., Chen, L.J., Liu, D.T., Lai, T.Y., Sakurada, Y., Tanaka, H.; J-MICC Study Group.: Detailed Yoneyama, S., Cheng, C.Y., Cackett, P., Yeo, I.Y., analysis of Japanese population substructure with a Tay, W.T., Cornes, B.K., Vithana, E.N., Aung, T., focus on the southwest islands of Japan. PLoS One, Matsuo, K., Matsuda, F., Wong, T.Y., Iijima, H., 7: e35000, 2012. (PMID: 22509376) Pang, C.P., Yoshimura, N.: Association of genetic J102. Nogami, N., Hotta, K., Segawa, Y., Takigawa, variants on 8p21 and 4q12 with age-related macular N., Hosokawa, S., Oze, I., Fujii, M., Ichihara, E., degeneration in asian populations. Invest Shibayama, T., Tada, A., Hamada, N., Uno, M., Ophthalmol Vis Sci, 53: 6576-6581, 2012. (PMID: Tamaoki, A., Kuyama, S., Ikeda, G., Osawa, M., 22930721) Takata, S., Tabata, M., Tanimoto, M., Kiura, K.: J096. Nakata, K., Takami, A., Espinoza, J.L., Phase II study of irinotecan and amrubicin in Matsuo, K., Morishima, Y., Fukuda, T., Kodera, Y., patients with relapsed non-small cell lung cancer: Miyamura, K., Nakao, S. for the JMDP.: The Okayama Lung Cancer Study Group Trial 0402. recipient CXCL10 +1642CG variation predicts Acta Oncol, 51: 768-773, 2012. (PMID: 22283472) survival outcomes after HLA-fully-matched J103. Ochi, N., Hotta, K., Takigawa, N., Oze, I., unrelated bone marrow transplantation. Clin Fujiwara, Y., Ichihara, E., Hisamoto, A., Tabata, Immunol, 146: 104-111, 2013. (PMID: 23291247) M., Tanimoto, M., Kiura, K.: Treatment-related J097. Narita, Y., Murata, T., Ryo, A., Kawashima, death in patients with small-cell lung cancer in D., Sugimoto, A., Kanda, T., Kimura, H., Tsurumi, phase III trials over the last two decades. PLoS One, T.: Pin1 interacts with the Epstein-Barr virus DNA 7: e42798, 2012. (PMID: 22880112) polymerase catalytic subunit and regulates viral J104. Odaka, C., Loranger, A., Takizawa, K., DNA replication. J Virol, 87: 2120-2127, 2012. Ouellet, M., Tremblay, M.J., Murata, S., Inoko, A., (PMID: 23221557) Inagaki, M., Marceau, N.: Keratin 8 is required for J098. Neise, D., Sohn, D., Stefanski, A., Goto, H., the maintenance of architectural structure in thymus Inagaki, M., Wesselborg, S., Budach, W., Stühler, epithelium. PLoS One, 8: e75101, 2013. (PMID: K., Jänicke, R.U.: The p90 ribosomal S6 kinase 24086449) (RSK) inhibitor BI-D1870 prevents gamma J105. Ohta, M., Abe, A., Ohno, F., Hasegawa, Y., irradiation-induced apoptosis and mediates Tanaka, H., Maseki, S., Kondo, E., Kurita, K., senescence via RSK- and p53-independent Nakanishi, H.: Positive and negative regulation of 61 podoplanin expression by TGF-β and histone interferon-γ staining analysis of donor-specific deacetylase inhibitors in oral and pharyngeal T-cell responses in liver transplant recipients. squamous cell carcinoma cell lines. Oral Oncol, 49: Transplant Proc, 44: 548-554, 2012. (PMID: 20-26, 2012. (PMID: 22840788) 22410067) J106. Ojima, M., Hanioka, T., Tanaka, H.: J112. Ono, H., Chihara, D., Chiwaki, F., Sasaki, Necessity and readiness for smoking cessation H., Yanagihara, K., Yoshida, T., Saeki, N., Matsuo, intervention in dental clinics in Japan. J Epidemiol, K.: Missense allele of a single 22: 57-63, 2012. (PMID: 22156286) nucleotidepolymorphism rs2294008 attenuated anti-tumor effects of prostate stemcell antigen J107. Okada, R., Kawai, S., Naito, M., Hishida, A., (PSCA) gene in gallbladder cancer cells. J Carcinog, Hamajima, N., Shinchi, K., Chowdhury, Turin, T., 12: 4, 2013. (PMID: 23599686) Suzuki, S., Mantjoro, E.M., Toyomura, K., Arisawa, K., Kuriyama, N., Hosono, S., Mikami, J113. Ozaki, H., Matsuzaki, H., Ando, H., Kaji, H., H., Kubo, M., Tanaka, H., Wakai, K.: Matrix Nakanishi, H., Ikehara, Y., Narimatsu, H.: metalloproteinase-9 gene polymorphisms and Enhancement of metastatic ability by ectopic chronic kidney disease. Am J Nephrol, 36: expressionof ST6GalNAcI on a gastric cancer cell 444-450, 2012. (PMID: 23128247) line in a mouse model. Clin Exp Metastas, 29: 229-238, 2012. (PMID: 22228572) J108. Okada, R., Wakai, K., Naito, M., Morita, E., Kawai, S., Hamajima, N., Hara, M., Takashima, J114. Ozaki, S., Takigawa, N., Ichihara, E., Hotta, N., Suzuki, S., Takezaki, T., Ohnaka, K., Arisawa, K., Oze, I., Kurimoto, E., Fushimi, S., Ogino, T., K., Hirohata, H., Matsuo, K., Mikami, H., Kubo, Tabata, M., Tanimoto, M., Kiura, K.: Favorable M., Tanaka, H.: Pro/anti-inflammatory cytokine response of heavily treated Wilms' tumor to gene polymorphisms and chronic kidney disease: a paclitaxel and carboplatin. Onkologie, 35: 283-286, cross-sectional study. BMC Nephrol, 13: 2, 2012. 2012. (PMID: 22868510) (PMID: 22230215) J115. Oze, I., Matsuo, K., Ito, H., Wakai, K., J109. Okada, Y., Terao, C., Ikari, K., Kochi, Y., Nagata, C., Mizoue, T., Tanaka, K., Tsuji, I., Ohmura, K., Suzuki, A., Kawaguchi, T., Stahl, Tamakoshi, A., Sasazuki, S., Inoue, M., Tsugane, E.A., Kurreeman, F.A., Nishida, N., Ohmiya, H., S.; for the Research Group for the Development Myouzen, K., Takahashi, M., Sawada, T., Nishioka, and Evaluation of Cancer Prevention Strategies in Y., Yukioka, M., Matsubara, T., Wakitani, S., Japan.: Cigarette smoking and esophageal cancer Teshima, R., Tohma, S., Takasugi, K., Shimada, K., risk: an evaluation based on a systematic review of Murasawa, A., Honjo, S., Matsuo, K., Tanaka, H., epidemiologic evidence among the Japanese Tajima, K., Suzuki, T., Iwamoto, T., Kawamura, Y., population. Jpn J Clin Oncol, 42: 63-73, 2012. Tanii, H., Okazaki, Y., Sasaki, T., Gregersen, P.K., (PMID: 22131340) Padyukov, L., Worthington, J., Siminovitch, K.A., J116. Oze, I., Matsuo, K., Kawakita, D., Hosono, Lathrop, M., Taniguchi, A., Takahashi, A., S., Ito, H., Watanabe, M., Hatooka, S., Hasegawa, Tokunaga, K., Kubo, M., Nakamura, Y., Kamatani, Y., Shinoda, M., Tajima, K., Tanaka, H. Coffee and N., Mimori, T., Plenge, R.M., Yamanaka, H., green tea consumption is associated with upper Momohara, S., Yamada, R., Matsuda, F., aerodigestive tract cancer in Japan. International Yamamoto, K.: Meta-analysis identifies nine new journal of cancer Journal international du cancer, loci associated with rheumatoid arthritis in the 2013, Dec 6. doi: 10.1002/ijc.28653. [Epub ahead Japanese population. Nat Genet, 44: 511-516, 2012. of print] (PMID:24310779) (PMID: 22446963) J117. Patnode, M., Yu, S-Y., Cheng, C-W., Ho, J110. Okamoto, S., Amaishi, Y., Goto, Y., Ikeda, H., M-Y., Tegesjö, L., Sakuma, K., Uchimura, K., Fujiwara, H., Kuzushima, K., Yasukawa, M., Khoo, K-H., Kannagi, R., Rosen, S.: KSGal6ST Shiku, H., Mineno, J.: A promising vector for TCR generates galactose-6-O-sulfate in high endothelial gene therapy: differential effect of siRNA, 2A venules but does not contribute to L-selectin peptide, and disulfide bond on the introduced TCR dependent lymphocyte homing. Glycobiology, 23: expression. Mol Ther Nucleic Acids, 1: e63, 2012. 381-394, 2013. (PMID: 23254996) (PMID: 23250361) J118. Permuth-Wey, J., Lawrenson, K., Shen, H.C., J111. Okanami, Y., Tsujimura, K., Mizuno, S., Velkova, A., Tyrer, J.P., Chen, Z., Lin, H.Y., Ann, Tabata, M., Isaji, S., Akatsuka, Y., Kuzushima, K., Chen, Y., Tsai, Y.Y., Qu, X., Ramus, S.J., Karevan, Takahashi, T., Uemoto, S.: Intracellular R., Lee, J., Lee, N., Larson, M.C., Aben, K.K., 62

Anton-Culver, H., Antonenkova, N., Antoniou, J119. Peters, U., Jiao, S., Schumacher, F.R., A.C., Armasu, S.M.; stralian Cancer Study; Hutter, C.M., Aragaki, A.K., Baron, J.A., Berndt, stralian Ovarian Cancer Study, Bacot, F., S.J., Bezieau, S., Brenner, H., Butterbach, K., Baglietto, L., Bandera, E.V., Barnholtz-Sloan, J., Caan, B.J., Carlson, C.S., Casey, G., Chan, A.T., Beckmann, M.W., Birrer, M.J., Bloom, G., Chang-Claude, J., Chanock, S.J., Chen, L.S., Bogdanova, N., Brinton, L.A., Brooks-Wilson, A., GCoetzee, G.A., Coetzee, A.G., Conti, D.V., Curtis, Brown, R., Butzow, R., Cai, Q., Campbell, I., K., Duggan, D., Edwards, T., Fuchs, C.S., Chang-Claude, J., Chanock, S., Chenevix-Trench, Gallinger, S., Giovannucci, E.L., Gogarten, S.M., G., Cheng, J.Q., Cicek, M.S., Coetzee, G.A.; Gruber, S.B., Haile, R.B., Harrision, T.A., Hayes, Consortium of Investigators of Modifiers of R.B., Henderson, B.E., Hoffmeister, M., Hopper, BRCA1/2, Cook, L.S., Couch, F.J., Cramer, D.W., J.L., Hudson, T.J., Hunter, D.J., Jackson, R.D., Cunningham, J.M., Dansonka-Mieszkowska, A., Jenkins, M.A., Kolonel, L.N., Kooperberg, C., Despierre, E., Doherty, J.A., Drk, T., du Bois, A., Kury, S., Jee, S.H., Jia, W.H., LCroix, A.Z., Laruie, Drst, M., Easton, D.F., Eccles, D., Edwards, R., C.C., Laurie, C.A., Le Marchand, L., Lemier, M., Ekici, A.B., Fasching, P.A., Fenstermacher, D.A., Levine, D., Lindor, N.M., Liu, Y., Ma, J., Makar, Flanagan, J.M., Garcia-Closas, M., K.W., Matsuo, K., Newocmb, P.A., Potter, J.D., Gentry-Maharaj, A., Giles, G.G., Glasspool, R.M., Prentice, R.L., Qu, C., Rohan, T., Rosse, S.A., Gonzalez-Bosquet, J., Goodman, M.T., Gore, M., Schoen, R.E., Seminara, D., Shrubsole, M., Shu, Grski, B., Gronwald, J., Hall, P., Halle, M.K., X.O., Slattery, M.L., Taberna, D., Thibodeau, S.N., Harter, P., Heitz, F., Hillemanns, P., Hoatlin, M., Ulrich, C.M., Vijayaraghavan, R., Weir, B., White, Hgdall, C.K., Hgdall, E., Hosono, S., Jakubowska, E., Xiang, Y., Zanke, B.W., Zeng, Y.X., Zhang, B., A., Jensen, A., Jim, H., Kalli, K.R., Karlan, B.Y., Zheng, W., Hsu, L.: Identification of genetic Kaye, S.B., Kelemen, L.E., Kiemeney, L.A., susceptibility loci for colorectal tumors in a Kikkawa, F., Konecny, G.E., Krakstad, C., Krger, genome-wide meta-analysis. Gastroenterology, 144: Kjaer, S., Kupryjanczyk, J., Lambrechts, D., 799-807, 2013. (PMID: 23266556) Lambrechts, S., Lancaster, J.M., Le, N.D., J120. Pham, N.M., Mizoue, T., Tanaka, K., Tsuji, I., Leminen, A., Levine, D.A., Liang, D., Kiong, Lim, Tamakoshi, A., Matsuo, K., Ito, H., Wakai, K., B., Lin, J., Lissowska, J., Lu, K.H., Lubiгki, J., Nagata, C., Sasazuki, S., Inoue, M., Tsugane, S.: Lurie, G., Massuger, L.F., Matsuo, K., McGuire, V., Physical activity and colorectal cancer risk: an McLaughlin, J.R., Menon, U., Modugno, F., evaluation based on a systematic review of Moysich, K.B., Nakanishi, T., Narod, S.A., epidemiologic evidence among the Japanese Nedergaard, L., Ness, R.B., Nevanlinna, H., population. Jpn J Clin Oncol, 42: 2-13, 2012. Nickels, S., Noushmehr, H., Odunsi, K., Olson, (PMID: 22068300) S.H., Orlow, I., Paul, J., Pearce, C.L., Pejovic, T., Pelttari, L.M., Pike, M.C., Poole, E.M., Raska, P., J121. Pharoah, P.D., Tsai, Y.Y., Ramus, S.J., Renner, S.P., Risch, H.A., Rodriguez-Rodriguez, Phelan, C.M., Goode, E.L., Lawrenson, K., L., Anne Rossing, M., Rudolph, A., Runnebaum, Buckley, M., Fridley, B.L., Tyrer, J.P., Shen, H., I.B., Rzepecka, I.K., Salvesen, H.B., Schwaab, I., Weber, R., Karevan, R., Larson, M.C., Song, H., Severi, G., Shridhar, V., Shu, X.O., Shvetsov, Y.B., Tessier, D.C., Bacot, F., Vincent, D., Cunningham, Sieh, W., Song, H., Southey, M.C., Spiewankiewicz, J.M., Dennis, J., Dicks, E; Australian Cancer B., Stram, D., Sutphen, R., Teo, S.H., Terry, K.L., Study; Australian Ovarian Cancer Study Group, Tessier, D.C., Thompson, P.J., Tworoger, S.S., van Aben, K.K., Anton-Culver, H., Antonenkova, N., Altena, A.M., Vergote, I., Vierkant, R.A., Vincent, Armasu, S.M., Baglietto, L., Bandera, E.V., D., Vitonis, A.F., Wang-Gohrke, S., Palmieri, Beckmann, M.W., Birrer, M.J., Bloom, G., Weber, R., Wentzensen, N., Whittemore, A.S., Wik, Bogdanova, N., Brenton, J.D., Brinton, L.A., E., Wilkens, L.R., Winterhoff, B., Ling, Woo, Y., Brooks-Wilson, A., Brown, R., Butzow, R., Wu, A.H., Xiang, Y.B., Yang, H.P., Zheng, W., Campbell, I., Carney, M.E., Carvalho, R.S., Ziogas, A., Zulkifli, F., Phelan, C.M., Iversen, E., Chang-Claude, J., Chen, Y.A., Chen, Z., Chow, Schildkraut, J.M., Berchuck, A., Fridley, B.L., W.H., Cicek, M.S., Coetzee, G., Cook, L.S., Cramer, Goode, E.L., Pharoah, P.D., Monteiro, A.N., D.W., Cybulski, C., Dansonka-Mieszkowska, A., Sellers, T.A., Gayther, S.A.: Identification and Despierre, E., Doherty, J.A., Drk, T., du Bois, A., molecular characterization of a new ovarian cancer Drst, M., Eccles, D., Edwards, R., Ekici, A.B., susceptibility locus at 17q21.31. Nat Commun, 4: Fasching, P.A., Fenstermacher, D., Flanagan, J., 1627, 2013. (PMID: 23535648) Gao, Y.T., Garcia-Closas, M., Gentry-Maharaj, A., Giles, G., Gjyshi, A., Gore, M., Gronwald, J., Guo, 63

Q., Halle, M.K., Harter, P., Hein, A., Heitz, F., E-selectin ligand expression in colon cancer cells Hillemanns, P., Hoatlin, M., Hgdall, E., Hgdall, undergoing EGF/bFGF-induced C.K., Hosono, S., Jakubowska, A., Jensen, A., epithelial-mesenchymal transition. Proc Natl Acad Kalli, K.R., Karlan, B.Y., Kelemen, L.E., Kiemeney, Sci USA, 109: 7776-7781, 2012. (PMID: L.A., Kjaer, S.K., Konecny, G.E., Krakstad, C., 22547830) Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., J126. Sakuma, K., Chen, G.Y., Aoki, M., Kannagi, Le, N.D., Lee, N., Lee, J., Leminen, A., Lim, B.K., R.: Induction of 6-sulfated glycans with cell Lissowska, J., Lubiгki, J., Lundvall, L., Lurie, G., adhesion activity via T-bet and GATA-3 in human Massuger, L.F., Matsuo, K., McGuire, V., helper T cells. Biochem Biophys Acta, 1820: McLaughlin, J.R., Menon, U., Modugno, F., 841-848, 2012. (PMID: 23088960) Moysich, K.B., Nakanishi, T., Narod, S.A., Ness, R.B., Nevanlinna, H., Nickels, S., Noushmehr, H., J127. Sakuma, K., Furuhashi, T., Kondo, S., Yabe, Odunsi, K., Olson, S., Orlow, I., Paul, J., Pejovic, U., Ohmori, K., Ito, H., Aoki, M., Morita, A., T., Pelttari, L.M., Permuth-Wey, J., Pike, M.C., Kannagi, R.: Sialic acid cyclization of human Poole, E.M., Qu, X., Risch, H.A., Th homing receptor glycan associated with Rodriguez-Rodriguez, L., Rossing, M.A., Rudolph, recurrent exacerbations of atopic dermatitis. J A., Runnebaum, I., Rzepecka, I.K., Salvesen, H.B., Dermatol Sci, 68: 187-193, 2012. (PMID: Schwaab, I., Severi, G., Shen, H., Shridhar, V., 23088960) Shu, X.O., Sieh, W., Southey, M.C., Spellman, P., J128. Sasazuki, S., Charvat, H., Hara, A., Wakai, Tajima, K., Teo, S.H., Terry, K.L., Thompson, P.J., K., Nagata, C., Nakamura, K., Tsuji, I., Sugawara, Timorek, A., Tworoger, S.S., van Altena, A.M., van Y., Tamakoshi, A., Matsuo, K., Oze, I., Mizoue, T., den Berg, D., Vergote, I., Vierkant, R.A., Vitonis, Tanaka, K., Inoue, M., Tsugane, S.. Diabetes A.F., Wang-Gohrke, S., Wentzensen, N., mellitus and cancer risk: Pooled analysis of eight Whittemore, A.S., Wik, E., Winterhoff, B., Woo, cohort studies in Japan. Cancer Sci, 2013, Jul 26. Y.L., Wu, A.H., Yang, H.P., Zheng, W., Ziogas, A., doi: 10.1111/cas.12241. [Epub ahead of print] Zulkifli, F., Goodman, M.T., Hall, P., Easton, D.F., (PMID:23889822) Pearce, C.L., Berchuck, A., Chenevix-Trench, G., Iversen, E., Monteiro, A.N., Gayther, S.A., J129. Sato, F., Sawamura, M., Ojima, M., Tanaka, Schildkraut, J.M., Sellers, T.A.: GWAS K., Hanioka, T., Tanaka, H., Matsuo, K.: Smoking meta-analysis and replication identifies three new increases risk of tooth loss: A meta-analysis of the susceptibility loci for ovarian cancer. Nat Genet, 45: literature. World J Meta-analysis, 1: 16-26, 2013. 362-370, 2013. (PMID: 23535730) J130. Sekido Y.: Molecular genetics of malignant J122. Saito, K., Sakaguchi, M., Iioka, H., Matsui, mesothelioma. eLS, WILEY -ONLINE LIBRARY, M., Nakanishi, H., Huh, N.H., Kondo, E.: 2012. Published Online: 16 JUL 2012. Coxsackie and adenovirus receptor is a critical J131. Seto, M., Yoshida, N., Umino, A., Karube, K., regulator for the survival and growth of oral Utsunomiya, A.: Molecular characterization of squamous carcinoma cells. Oncogene, 2013. Mar T/NK-cell malignancies. Rinsho Ketsueki, 54: 18, doi: 10.1038/onc.2013.66. [Epub ahead of print] 628-635, 2013. (PMID: 23912345) (PMID: 23503452) J132. Seto, M.: Cyclin D1-negative mantle cell J123. Saito, K., Takigawa, N., Ohtani, N., Iioka, H., lymphoma. Blood, 121: 1249-1250, 2013. (PMID: Tomita, Y., Ueda, R., Fukuoka, J., Kuwahara, K., 23429984) Ichihara, E., Kiura, K., Kondo, E.: Anti-tumor impact of p14ARF on gefitinib-resistant non-small J133. Shen, H., Fridley, B.L., Song, H., cell lung cancers. Mol Cancer Ther, 12:1616-1628, Lawrenson, K., Cunningham, J.M., Ramus, S.J., 2013. (PMID: 23761220) Cicek, M.S., Tyrer, J., Stram, D., Larson, M.C., Kbel, M; PRACTICAL Consortium, Ziogas, A., J124. Saito, S., Murata, T., Kanda, T., Isomura, H., Zheng, W., Yang, H.P., Wu, A.H., Wozniak, E.L., Narita, Y., Sugimoto, A., Kawashima, D., Tsurumi, Ling, Woo, Y., Winterhoff, B., Wik, E., Whittemore, T.: Epstein-Barr virus deubiquitinase downregulates A.S., Wentzensen, N., Palmieri, Weber, R., Vitonis, TRAF6-mediated NF-κB signaling during A.F., Vincent, D., Vierkant, R.A., Vergote, I., Van productive replication. J Virol, 87: 4060-4070, 2013. Den Berg, D., Van Altena, A.M., Tworoger, S.S., (PMID: 23365429) Thompson, P.J., Tessier, D.C., Terry, K.L., Teo, J125. Sakuma, K., Aoki, M., Kannagi, R.: S.H., Templeman, C., Stram, D.O., Southey, M.C., Transcription factors c-Myc and CDX2 mediate Sieh, W., Siddiqui, N., Shvetsov, Y.B., Shu, X.O.,

Shridhar, V., Wang-Gohrke, S., Severi, G., J135. Shimazu, T., Sasazuki, S., Wakai, K., Schwaab, I., Salvesen, H.B., Rzepecka, I.K., Tamakoshi, A., Tsuji, I., Sugawara, Y., Matsuo, K., Runnebaum, I.B., Anne Rossing, M., Nagata, C., Mizoue, T., Tanaka, K., Inoue, M., Rodriguez-Rodriguez, L., Risch, H.A., Renner, Tsugane, S.; for the Research Group for the S.P., Poole, E.M., Pike, M.C., Phelan, C.M., Development and Evaluation of Cancer Pelttari, L.M., Pejovic, T., Paul, J., Orlow, I., Prevention Strategies in Japan.: Alcohol Zawiah, Omar, S., Olson, S.H., Odunsi, K., drinking and primary liver cancer: A pooled Nickels, S., Nevanlinna, H., Ness, R.B., Narod, analysis of four Japanese cohort studies. Int J S.A., Nakanishi, T., Moysich, K.B., Monteiro, A.N., Cancer, 130: 2645-2653, 2012. (PMID: 21702041) Moes-Sosnowska, J., Modugno, F., Menon, U., J136. Shitara, K., Ikeda, J., Kondo, C., Takahari, McLaughlin, J.R., McGuire, V., Matsuo, K., Mat D., Ura, T., Muro, K., Matsuo, K.: Reporting Adenan, N.A., Massuger, L.F., Lurie, G., Lundvall, patient characteristics and stratification factors in L., Lubiгki, J., Lissowska, J., Levine, D.A., randomized trials of systemic chemotherapy for Leminen, A., Lee, A.W., Le, N.D., Lambrechts, S., advanced gastric cancer. Gastric Cancer, 15: Lambrechts, D., Kupryjanczyk, J., Krakstad, C., 137-143, 2012 . (PMID: 21842172) Konecny, G.E., Krger Kjaer, S., Kiemeney, LA.,. Kelemen, L.E., Keeney. G.L., Karlan, B.Y., J137. Shitara, K., Ikeda, J., Yokota, T., Takahari, Karevan, R., Kalli, K.R., Kajiyama, H., Ji, B.T., D., Ura, T., Muro, K., Matsuo, K.: Progression-free Jensen, A., Jakubowska, A., Iversen, E., Hosono, survival and time to progression as surrogate S., Hgdall, C.K., Hgdall, E., Hoatlin, M., markers of overall survival in patients with Hillemanns, P., Heitz, F., Hein, R., Harter, P., advanced gastric cancer: analysis of 36 randomized Halle, M.K., Hall, P., Gronwald, J., Gore, M., trials. Invest New Drug, 30: 1224-1231, 2012. Goodman, M.T., Giles, G.G., Gentry-Maharaj, A., (PMID: 21350803) Garcia-Closas, M., Flanagan, J.M., Fasching, J138. Shitara, K., Ito, S., Misawa, K., Ito, Y., Ito, P.A., Ekici, A.B., Edwards, R., Eccles, D., Easton, H., Hosono, S., Watanabe, M., Tajima, K., Tanaka, D.F., Drst, M., du Bois, A., Drk, T., Doherty, J.A., H., Muro, K., Matsuo, K.: Genetic polymorphism Despierre, E., Dansonka-Mieszkowska, A., of IGF-I predicts recurrence in patients with gastric Cybulski, C., Cramer, D.W., Cook, L.S., Chen, X., cancer who have undergone curative gastrectomy. Charbonneau, B., Chang-Claude, J., Campbell, I., Ann Oncol, 23: 659-664, 2012. (PMID: 21690232) Butzow, R., Bunker, C.H., Brueggmann, D., Brown, R., Brooks-Wilson, A., Brinton, L.A., J139. Shitara, K., Matsuo, K., Muro, K., Doi, T., Bogdanova, N., Block, M.S., Benjamin, E., Ohtsu, A.: Progression-free survival Beesley, J., Beckmann, M.W., Bandera, E.V., andpost-progression survival in patients with Baglietto, L., Bacot, F., Armasu, S.M., advanced gastric cancer treated firstwith -line Antonenkova, N., Anton-Culver, H., Aben, K.K., chemotherapy. J Cancer Res Clin, 139: 1383-1389, Liang, D., Wu, X., Lu, K., Hildebrandt, M.A.; 2013. (PMID: 23708301) stralian Ovarian Cancer Study Group; stralian J140. Shitara, K., Sawaki, A., Matsuo, K., Kondo, Cancer Study, Schildkraut, J.M., Sellers, T.A., C., Takahari, D., Ura, T., Tajika, M., Niwa, Y., Huntsman, D., Berchuck, A., Chenevix-Trench, G., Muro, K.: A retrospective comparison of S-1 plus Gayther, S.A., Pharoah, P.D., Laird, P.W., Goode, cisplatin and capecitabine plus cisplatin for patients E.L., Leigh, Pearce, C.: Epigenetic analysis leads with advanced or recurrent gastric cancer. Int J Clin to identification of HNF1B as a subtype-specific Oncol, 18: 539-546, 2013. (PMID: 22552360) susceptibility gene for ovarian cancer. Nat Commun, 4: 1628, 2013. (PMID: 23535649) J141. Shitara, K., Yatabe, Y., Matsuo, K., Sugano, M., Kondo, C., Takahari, D., Ura, T., Tajika, M., J134. Shi, J., Sung, H., Zhang, B., Lu, W., Choi, Ito, S., Muro, K.: Prognosis of patients with J.Y., Xiang, Y.B., Kim, M.K., Iwasaki, M., Long, J., advanced gastric cancer by HER2 status and Ji, B.T., Park, S.K., Zheng, Y., Tsugane, S., Yoo, trastuzumab treatment. Gastric Cancer, 16: 261-267, K.Y., Wang, W., Noh, D.Y., Han, W., Kim, S.W., 2013. (PMID: 22797858) Lee, M.H., Lee, J.W., Lee, J.Y., Shen, C.Y., Matsuo, K., Ahn, S.H., Gao, Y.T., Shu, X.O., Cai, Q., Kang, J142. Shitara, K., Yuki, S., Tahahari, D., D., Zheng, W.: New breast cancer risk variant Nakamura, M., Kondo, C., Tsuda, T., Kii, T., Tsuji, discovered at 10q25 in East Asian women cancer. Y., Utsunomiya, S., Ichikawa, D., Hosokawa, A., Epidemiol Biomarker Prev, 22: 1297-1303, 2013. Ishiguro, A., Sakai, D., Hironaka, S., Oze, I., (PMID: 23677579) Matsuo, K., Muro, K. Randomised phase II study comparing dose-escalated weekly paclitaxel vs 65 standard-dose weekly paclitaxel for patients with J150. Tanaka, I., Osada, H., Fujii, M., Fukatsu, A., previously treated advanced gastric cancer. Brit J Hida, T., Horio, Y., Kondo, Y., Sato, A., Hasegawa, Cancer, 110: 271-277, 2014. (PMID:24281004) Y., Tsujimura, T., Sekido, Y.: LIM-domain protein AJUBA suppresses malignant mesothelioma cell J143. Suda, K., Tomizawa, K., Osada, H., Maehara, proliferation via Hippo signaling cascade. Y., Yatabe, Y., Sekido, Y., Mitsudomi, T.: Oncogene, 2013 Dec 16, [Epub ahead of print] Conversion from the “oncogene addiction” to “drug (PMID: 24336325) addiction” by intensive inhibition of the EGFR and MET in lung cancer with activating EGFR mutation. J151. Tanaka, K., Tamiya-Koizumi, K., Hagiwara, Lung cancer, 76: 292-299, 2012. (PMID: K., Ito, H., Takagi, A., Kojima, T., Suzuki, M., 22133747) Iwaki, S., Fujii, S., Nakamura, M., Banno, Y., Kannagi, R., Tsurumi, T., Kyogashima, M., J144. Sueta, A., Ito, H., Islam, T., Hosono, S., Murate, T.: Role of down-regulated neutral Watanabe, M., Hirose, K., Fujita, T., Yatabe, Y., ceramidase during all-trans retinoic acid-induced Iwata, H., Tajima, K., Tanaka, H., Matsuo, K.: neuronal differentiation in SH-SY5Y Differential impact of body mass index and its neuroblastoma cells. J Biochem, 151: 611-6200, change on the risk of breast cancer by molecular 2012. (PMID: 22451680) subtype: A case-control study in Japanese women. SpringerPlus, 1: 39, 2012 J152. Tanaka, M., Ma, E., Tanaka, H., Ioka, A., Nakahara, T., Takahashi, H.: Trends of stomach J145. Sueta, A., Ito, H., Kawase, T., Hirose, K., cancer mortality in eastern Asia in 1950-2004: Hosono, S., Yatabe, Y., Tajima, K., Tanaka, H., Comparative study of Japan, Hong Kong and Iwata, H., Iwase, H., Matsuo, K.: A genetic risk Singapore using age, period and cohort analysis. Int predictor for breast cancer using a combination of J Cancer, 130: 930-936, 2012. (PMID: 21425256) low-penetrance polymorphisms in a Japanese population. Breast Cancer Res Tr, 132: 711-721, J153. Taniguchi, C., Tanaka, H., Oze, I., Ito, H., 2012. (PMID: 22160591) Saka, H., Tachibana, K., Tokoro, A., Nozaki, Y., Nakamichi, N., Suzuki, Y., Suehisa, H., J146. Sugimoto, A., Sato, Y., Kanda, T., Murata, T., Sakakibara, H.: Factors associated with weight Narita, Y., Kawashima, D., Kimura, H., Tsurumi, gain after smoking cessation therapy in Japan. Nurs T.: Different distributions of Epstein-Barr virus Res, 62: 414-421, 2013. (PMID: 24165217) early and late gene transcripts within viral replication compartments. J Virol, 87: 6693-6699, J154. Tanikawa, C., Matsuo, K., Kubo, M., 2013. (PMID: 23552415) Takahashi, A., Ito, H., Tanaka, H., Yatabe, Y., Yamao, K., Kamatani, N., Tajima, K., Nakamura, J147. Taguchi, O., Tsujimura, K., Kontani, K., Y., Matsuda, K.: Impact of PSCA variation on Harada, Y., Nomura, S., Ikeda, H., Morita, A., gastric ulcer susceptibility. Plos One, 8: e63698, Sugiura, H., Hayashi, N., Yatabe, Y., Seto, M., 2013. (PMID: 23704932) Tatematsu, M., Takahashi, T., Fukushima, A.: Behavior of bone marrow-derived cells following in J155. Tcherniuk, S., Fiser, A-L., Derouazi, M., vivo transplantation: Differentiation into stromal Toussaint, B., Wang, Y., Wojtal, I., Kondo, E., cells with roles in organ maintenance. Am J Pathol, Szolajska, E., Chroboczek, J.: Certain protein 1482: 1255-1262, 2013. (PMID: 23416163) transducing agents convert translocated proteins into cell killers. Acta Biochim Pol, 59: 433-439, J148. Takagi, M., Ueda, J., Hwang, J-H., 2012. (PMID: 22946029) Hashimoto, J., Izumikawa, M., Murakami, H., Sekido, Y., Shin-ya, K.: Tyrosyl-DNA J156. Terao, C., Ohmura, K., Ikari, K., Kochi, Y., phosphodiesterase 1 inhibitor from an anamorphic Maruya, E., Katayama, M., Yurugi, K., Shimada, fungus. J Nat Prod, 75: 764-767, 2012. (PMID: K., Murasawa, A., Honjo, S., Takasugi, K., Matsuo, 22390627) K., Tajima, K., Suzuki, A., Yamamoto, K., Momohara, S., Yamanaka, H., Yamada, R., Saji, J149. Tamanaka, T., Oka, Y., Fujiki, F., Tsuboi, A., H., Matsuda, F., Mimori, T.: ACPA-negative RA Katsuhara, A., Nakajima, H., Hosen, N., Nishida, consists of two genetically distinct subsets based on S., Lin, Y.H., Tachino, S., Akatsuka, Y., RF positivity in Japanese. Plos One, 7: e40067, Kuzushima, K., Oji, Y., Kumanogoh, A., Sugiyama, 2012. (PMID: 22792215) H.: Recognition of a natural WT1 epitope by a modified WT1 peptide-specific T-cell receptor. J157. Teshima, K., Nara, M., Watanabe, A., Ito, M., Anticancer Res, 32: 5201-5209, 2012. (PMID: Ikeda, S., Hatano, Y., Oshima, K., Seto, M., 23225417) Sawada, K., Tagawa, H.: Dysregulation of BMI1 66 and microRNA-16 collaborate to enhance an 23412791) anti-apoptotic potential in the side population of J165. Yamada, T., Takeuchi, S., Fujita, N., refractory mantle cell lymphoma. Oncogene, 2013. Nakamura, A., Wang, W., Li, Q., Oda, M., May 20. doi: 10.1038/onc.2013.177. [Epub ahead Mitsudomi, T., Yatabe, Y., Sekido, Y., Yoshida, J., of print] (PMID: 23686310) Higashiyama, M., Noguchi, M., Uehara, H., J158. Toda, M., Kuo, C.H., Borman, S.K., Nishioka, Y., Sone, S., Yano, S.: Akt Richardson, R.M., Inoko, A., Inagaki, M., Collins, kinase-interacting protein1, a novel therapeutic A., Schneider, K., Ono, S.J.: Evidence that target for lung cancer with EGFR-activating and formation of Vimentin·Mitogen-activated Protein gatekeeper mutations. Oncogene, 32: 4427-4435, Kinase (MAPK) complex mediates mast cell 2013. (PMID: 23045273) activation following Fc{epsilon}RI/CC chemokine J166. Yamaguchi, T., Yanagisawa, K., Sugiyama, receptor 1 cross-talk. J Biol Chem, 287: R., Hosono, Y., Shimada, Y., Arima, C., Kato, S., 24516-24542, 2012. (PMID: 22613718) Tomida, S., Suzuki, M., Osada, H., Takahashi, T.: J159. Tokunaga, T., Shimada, K., Yamamoto, K., NKX2-1/TITF1/TTF-1-Induced ROR1 is required Chihara, D., Ichihashi, T., Oshima, R., Tanimoto, to sustain EGFR survival signaling in lung M., Iwasaki, T., Isoda, A., Sakai, A., Kobayashi, H., adenocarcinoma. Cancer Cell, 21: 348-361, 2012 Kitamura, K., Matsue, K., Taniwaki, M., (PMID: 22439932) Tamashima, S., Saburi, Y., Masunari, T., Naoe, T., J167. Yamamoto, K., Tsuzuki, S., Minami, Y., Nakamura, S., Kinoshita, T.: Retrospective Yamamoto, Y., Abe, A., Ohshima, K., Seto, M., analysis of prognostic factors for Naoe, T.: Functionally deregulated AML1/RUNX1 angioimmunoblastic T-cell lymphoma: a cooperates with BCR-ABL to induce a blastic multicenter cooperative study in Japan. Blood, 119: phase-like phenotype of chronic myelogenous 2837-2843, 2012. (PMID: 22308294) leukemia in mice. Plos One, 8: e74864, 2013. J160. Tsuzuki, S., Seto, M.: Expansion of (PMID: 24098673) functionally defined mouse hematopoietic stem and J168. Yamamura, T., Hikita, J., Bleakley, M., progenitor cells by a short isoform of Hirosawa, T., Sato-Otsubo, A., Torikai, H., RUNX1/AML1. Blood, 119: 727-735, 2012. Hamajima, T., Nannya, Y., Demachi-Okamura, A., (PMID: 22130803) Maruya, E., Saji, H., Yamamoto, Y., Takahashi, T., J161. Tsuzuki, S., Seto, M.: Emi, N., Morishima, Y., Kodera, Y., Kuzushima, K., TEL(ETV6)-AML1(RUNX1) initiates Riddell, S.R., Ogawa, S., Akatsuka, Y.: HapMap self-renewing fetal pro-B cells in association with a SNP Scanner: an online program to mine SNPs transcriptional program shared with embryonic responsible for cell phenotype. Tissue Antigens, 80: stem cells in mice. Stem Cells, 36: 236-247, 2013. 119-125, 2012. (PMID: 22568758) (PMID: 23135987) J169. Yamashita, Y., Ito, Y., Isomura, H., J162. Uemura, H., Hiyoshi, M., Arisawa, K., Takemura, N., Okamoto, A., Motomura, K., Yamaguchi, M., Naito, M., Kawai, S., Hamajima, Tsujiuchi, T., Natsume, A., Wakabayashi, T., N., Matsuo, K., Taguchi, N., Takashima, N., Toyokuni, S., Tsurumi, T.: Lack of presence of the Suzuki, S., Hirasada, K., Mikami, H., Ohnaka, K., human cytomegalovirus in human glioblastoma. Yoshikawa, A., Kubo, M., Tanaka, H.: Japan Mod Pathol, 2013. Epub ahead of print. (PMID: Multi-institutional Collaborative Cohort.: Gene 24336154) variants in PPARD and PPARGC1A are associated J170. Yanagisawa, K., Tomida, S., Matsuo, K., with timing of natural menopause in the general Arima, C., Kusumegi, M., Yokoyama, Y., Ko, S.B., Japanese population. Maturitas, 71: 369-375, 2012. Mizuno, N., Kawahara, T., Kuroyanagi, Y., (PMID: 22310107) Takeuchi, T., Goto, H., Yamao, K., Nagino, M., J163. Ueno, T., Toyooka, S., Suda, K., Soh, J., Tajima, K., Takahashi, T.: Seven-signal proteomic Yatabe, Y., Miyoshi, S., Matsuo, K., Mitsudomi, T.: signature for detection of operable pancreatic ductal Impact of age on epidermal growth factor receptor adenocarcinoma and their discrimination from mutation in lung cancer. Lung Cancer, 78: 207-211, autoimmune pancreatitis. Int J Proteomics, 2012: 2012. (PMID: 23036155) 510397, 2012. (PMID: 22675630) J164. Umino, A., Seto, M.: Array CGH reveals J171. Yokobori, T., Iinuma, H., Shimamura, T., clonal evolution of adult T-cell leukemia/lymphoma. Imoto, S., Sugimachi, K., Ishii, H., Iwatsuki, M., Methods Mol Biol, 973: 189-196, 2013. (PMID: Ota, D., Ohkuma, M., Iwaya, T., Nishida, N., Kogo, 67

J172. R., Sudo, T., Tanaka, F., Shibata, K., Toh, H., Shen, C.Y., Yu, J.C., Huang, C.S., Hous, M.F., Sato, T., Barnard, G.F., Fukagawa, T., Yamamoto, Hartman, M., Miao, H., Lee, S.C., Putti, T.C., S., Nakanishi, H., Sasaki, S., Miyano, S., Muir, K., Laphatananon, A., Stewart-Brown, S., Watanabe, T., Kuwano, H., Mimori, K., Pantel, K., Siriwanarangsan, P., Sangrajrang, S., Shen, H., Mori, M.: Plastin 3 is a novel marker for circulating Chen, K., Wu, P.E., Ren, Z., haiman, C.A., Sueta, tumor cells undergoing the epithelial–mesenchymal A., Kim, M., Khoo, U.S., Iwasaki, M., Pharaoah, transition and is associated with colorectal cancer P.D.P., Wen, Q., Hall, P., Shu, X.O., Easton, D.F., prognosis. Cancer Res, 73: 2059-2069, 2013. Kang, D.: Common genetic determinants of (PMID: 23378342) breast-cancer risk in East Asian women: a collaborative study of 23,637 breast cancer cases J173. Yoshida, N., Nishikori, M., Izumi, T., and 25,579 controls. Hum Mol Genet, 22: Imaizumi, Y., Sawayama, Y., Niino, D., Tashima, 2539-2550, 2013. (PMID: 23535825) M., Hoshi, S., Ohshima, K., Shimoyama, M., Seto, M., Tsukasaki, K.: Primary peripheral T-cell lymphoma, not otherwise: specified of the thyroid with autoimmune thyroiditis. Brit J Haematol, 161: 214-223, 2013. (PMID: 23432459) J174. Yoshida, N., Oda, M., Kuroda, Y., Katayama, Y., Okikawa, Y., Masunari, T., Fujiwara, M., Nishisaka, T., Sasaki, N., Sadahira, Y., Mihara, K., Asaoku, H., Matsui, H., Seto, M., Kimura, A., Arihiro, K., Sakai, A.: Clinical Significance of sIL-2R Levels in B-Cell Lymphomas. PLoS One. 8: e78730. 2013. (PMID: 24236041) J175. Yoshida, N., Umino, A., Liu, F., Arita, K., Karube, K., Tsuzuki, S., Ohshima, K., Seto, M.: Identification of multiple subclones in peripheral T-cell lymphoma, not otherwise specified with genomic aberrations. Cancer Medicine, 1: 289-294, 2012. (PMID: 23342278) J176. Yoshioka, S., Tsukamoto, Y., Hijiya, N., Nakada, C., Uchida, T., Matsuura, K., Takeuchi, I., Seto, M., Kawano, K., Moriyama, M.: Genomic profiling of oral squamous cell carcinoma by array-based comparative genomic hybridization. PLoS One, 8: e56165, 2013. (PMID: 23457519) J177. Yuasa, Y., Nagasaki, H., Oze, I., Akiyama, Y., Yoshida, S., Shitara, K., Ito, S., Hosono, S., Watanabe, M., Ito, H., Tanaka, H., Kang, D., Pan, K.F., You, W.C., Matsuo, K.: Insulin-like growth factor 2 hypomethylation of blood leukocyte DNA is associated with gastric cancer risk. Int J Cancer, 131: 2596-2603, 2012. (PMID: 22447362) J178. Zheng, W., Zhang, B., Cai, Q., Sung, H., Michailidou, K., Shi, J., Cho, J.Y., Long, J., Dennis, J., Hymphreys, M.K., Wang, Q., Lu, W., Gao, Y.T., Li, C., Cai, F., Park, S., Yoo, K.Y., Noh, D.Y., Han, W., Dunning, A.M., Benitez, J., Vincent, D., Bacot, F., Tessier, D., Kim, S.W., Le, M.H., Lee, J.W., Lee, J.Y., Xiang, Y.B., Zheng, Y., Wang, W., Ji, B.T., Matsuo, K., Ito, H., Iwata, H., Tanaka, H., Wu, A.H., Tseng, C.C., van den Berg, D., Stram, D.O., Teo, S.H., Yip, C.H., Kang, I.N., Wong, T.Y.,

1413-1419, 2013. (PMID: 23677068) Reviews and Books R012. Shinjo, K., Kondo, Y.: Clinical implications of epigenetic alterations in human thoracic R001. Fujii, M., Nakanishi, H., Toyoda, T., Tanaka, malignancies: epigenetic alterations in lung cancer. I., Kondo, Y., Osada, H., Sekido, Y.: Convergent Methods Mol Biol, 221-239, 2012. (PMID: signaling in the regulation of the connective tissue 22359296) growth factor in malignant mesothelioma: TGF- signaling and defects in the Hippo signaling cascade. Cell Cycle, 11: 3373-3379, 2012. (PMID: 22918238) R002. Fujii, M.: Exploration of a new drug that targets YAP. J Biochem, 152: 209-211, 2012. (PMID: 22761457) R003. Goto, H., Inagaki, M.: Method for generation of antibodies specific for site-and post-translational modifications. Monoclonal Antibodies: Methods and Protocols, Methods in Molecular Biology, vol. 1131, Springer Science+Business Media New York 2014. in press. R004. Goto, H., Inoko, A., Inagaki, M.: Cell cycle progression by the repression of primary cilia formation in proliferating cells. Cell Mol Life Sci, 70: 3893-3905, 2013. (PMID: 23475109) R005. Goto, H., Izawa, I., Li, P., Inagaki, M.: Novel regulation of checkpoint kinase 1: Is checkpoint kinase 1 a good candidate for anti-cancer therapy? Cancer Sci, 103: 1195-1200, 2012. (PMID: 22435685) R006. Murata, T., Tsurumi, T.: Epigenetic modification of the Epstein-Barr virus BZLF1 promoter regulates viral reactivation from latency. Front Genet, 4: 53, 2013. (PMID: 23577022) R007. Murata, T., Tsurumi, T.: Switching of EBV cycles between latent and lytic states. Rev Med Virol, Epub ahead of print, 2013. (PMID: 24339346) R008. Ohmuro-Matsuyama, Y., Inagaki, M., Ueda, H.: Detection of protein phosphorylation by open-sandwich immunoassay. Integrative Proteomics, ed. Leung, H.-C.E. InTech, 197-214, 2012. R009. Okamoto, Y., Kondo, Y.: Genetic and epigenetic alterations in inflammation-related cancers - General Mechanisms of Cancers. From Inflammation to Cancer, 29-48, 2012. R010. Sato, Y., Tsurumi, T.: Genome guardian p53 and viral infections. Rev Med Virol, 23: 213-220, 2012. (PMID: 23255396) R011. Sekido, Y.: Molecular pathogenesis of malignant mesothelioma. Carcinogenesis, 34: 69

Osada, H., Sekido, Y.: TGF-β synergizes with Abstracts for international conferences defects in the Hippo pathway by inducing CTGF expression. AACR Annual Meeting 2012, Chicago, 2012. A001. Akatsuka, Y., Taji, H., Morishima, Y., Miyamura, K., Kodera, Y., Emi, N., Takahashi, T., A009. Fukumoto, K., Ito, H., Park, C., Tanaka, H., Kinoshita, T., Kuzushima, K.: Vaccination Matsuo, K., Tajima, K., Takezaki, T.: Cigarette with minor histocompatibility antigen-derived smoke inhalation and lung cancer risk: Case-control peptides in post-transplant patients with study in Japan. 12th Annual AACR International hematological malignancies - preliminary results. Conference on Frontiers in Cancer Prevention 2nd International Workshop Biology, Prevention, Research, Washington, 2013. and Treatment of Relapse After Allogeneic A010. Goto, H., Kasahara, K., Izawa, I., Kiyono, Hematopoietic Stem Cell Transplantation, Bethesda, T., Watanabe, N., Elowe, S., Nigg, E.A., Inagaki, 2012. M.: Novel mitotic signalling crosstalk between A002. Arita, K., Seto, M.: New mouse models of PI3K-Akt pathway and Plk1. the 52nd Annual B-cell lymphoma using in vitro retroviral Meeting of the American Society for Cell Biology, transduction system. 9th AACR/JCA Joint San Francisco, 2012. Conference, Hawaii, 2013. A011. Goto, H.: Novel mitotic signaling crosstalk A003. Chihara, D., Asano, N., Kinoshita, T., between PI3K-Akt pathway and Plk1. 1st Maeda, Y., Matsue, K., Ohmachi, K., Okamoto, M., International Symposium on Protein Modifications Mizuno, I., Uchida, T., Nagai, H., Ogura, M., in Pathogenic Dysregulation of Signaling Suzuki, R.: Simplified MIPI is a valid prognostic (supported by Grant-in-Aid for Scientific Research index in the rituximab era: Multicenter MCL study on Innovative Area from MEXT), Tokyo, 2013. in Japan. Blood Abstracts 55th Annual Meeting, A012. Hirosawa, N., Sakamoto, T., Uemura, Y., New Orleans, 2013. Sakamoto, Y.: Proteomic analyses of adrenal and A004. Chihara, D., Ito, H., Matsuda, T., Katanoda, pituitary gland of rat exposed fenitrothion. The 26th K., Shibata, A., Saika, K., Sobue, T., Matsuo, K.: Annual Symposium of The Protein Society, San Decreasing trend in mortality of adult T-cell Diego, 2012. Leukemia/Lymphoma in Japan. T-cell Lymphoma A013. Inagaki, M., Goto, H.: Novel regulation of Forum, San Francisco, 2013 checkpoint kinase 1 (Chk1): Is Chk1 a good A005. Chihara, D., Izutsu, K., Kondo, E., Sakai, candidate for anti-cancer therapy? R., Mizuta, S., Yokoyama, K., Kaneko, H., Kato, K., Mini-Symposium on “Stress Signals & Responses”, Sakamaki, H., Suzuki, R., Suzumiya, J.: High-dose Abo Akademi University Center of Excellence chemotherapy with autologous stem cell “Cell stress and Molecular Aging”, Turku, 2012. transplantation for elderly patients with relapsed/ A014. Inagaki, M.: Intermediate filaments and site- refractory diffuse large b-cell lymphoma. 12th and phosphorylation state-specific antibodies. International onference of Malignant Lymphoma, Lecture at the University of Gothenburg, Switzerland, 2013. Gothenburg, 2012. A006. Chihara, D., Morton, L., Ito, H., A015. Inagaki, M.: Intermediate filaments and site- Weisenburger, T., Matsuo, K.: The difference in and phosphorylation state-specific antibodies. the incidence and the trend of States. American Global COE the 4th International Symposium, Association for Cancer Research Annual Meeting Nagoya, 2012. 2013, Washington, 2013. A016. Inagaki, M.: Pathophysiological roles of A007. Fujii, M., Nakanishi, H., Toyoda, T., intermediate filaments and intermediate filament Tanaka, I., Kondo, Y., Osada, H., Sekido, Y.: phosphorylation. International Meeting of the Convergent signaling in the regulatuion of German Society for Cell Biology, Leipzig, 2012. malignant mesothelioma growth through CTGF: TGF-β signaling and defects in the Hippo signaling A017. Inoko, A., Matsuyama, M., Goto, H., pathway. Ninth AACR-Japanese Cancer Ohmuro-Matsuyama, Y., Hayashi, Y., Enomoto, Association Joint Conference, Hawaii, 2012. M., Ibi, M., Urano, T., Yonemura, S., Kiyono, T., Izawa, I., Inagaki, M.: Trichoplein and Aurora A A008. Fujii, M., Toyoda, T., Nakanishi, H., block aberrant primary cilia assembly in Yatabe, Y., Sato, A., Hida, T., Tsujimura, T., proliferating cells. The 12th biennial Gordon 70

Conference on Intermediate Filaments, Lewiston, suppression via polycomb-mediated silencing 2012. mechanism in human glioma stem-like cells. JSPS Sapporo Cancer Epigenetics Seminar of the A3 A018. Ito, H., Gallus, S., Hosono, S., Oze, I., Foresight Program 2012, Sapporo, 2012. Fukumoto, K., Yatabe, Y., Hida, T., Mitsudomi, T., Negri, E., Vecchia, C., Tanaka, H., Matsuo, K.: A027. Katsushima, K., Shinjo, K., Ohka, F., Fujii, Time to first cigarette and lung cancer risk in Japan. M., Osada, H., Sekido, Y., Natsume, A., Kondo, Y.: 12th Annual AACR International Conference on Epigenetic regulation of miR-1275 through histone Frontiers in Cancer Prevention Research, H3 lysine 27 trimethylation during human glioma Washington, 2013. stem-like cell differentiation. AACR Annual Meeting 2012, Chicago, 2012. A019. Ito, H., Sueta, A., Iwata, H., Hosono, S., Oze, I., Watanabe, M., Iwase, H., Tanaka, H., A028. Katsushima, K.: Functional analysis of large Matsuo, K.: A genetic risk predictor for non-coding RNA associated with glioma stem cell breast cancer using a combination of maintenance. The 18th Korea-Japan Cancer low-penetrance polymorphisms in a Japanese Research Workshop, Gifu, 2013. population. An AACR Special Conference on A029. Kondo, E.: Development of the Post-GWAS Horizons in Molecular Epidemiology: Peptide-based anti-tumor DDS technology. Special Digging Deeper into the Environment. Hollywood, lecture (invited lecture at Stem Cell and 2012. Bioevaluation, WCU Biolodulation Program A020. Kanda, T., Murata, T., Tsurumi, T.: Animal Biotech Major, Dept Ag Biotech, CALS), Chromosome binding of Epstein-Barr virus EBNA1 Seoul national University, Seoul, 2013 protein is mediated by arginine residues within A030. Kondo, Y.: Epigenetic Plasticity and its chromosome binding domains. International clinical implications in human neoplasia. Ninth Congress on Oncogenic Herpesviruses and AACR-Japanese Cancer Association Joint Associated Diseases, Philadelphia, 2012. Conference, Hawaii, 2013. A021. Kanda, T., Murata, T., Tsurumi, T.: Roles A031. Kondo, Y.: Hepatitis virus infection affects of BART microRNAs in EBV-infected epithelial DNA methylation in mice with humanized livers. cells. 6th International Symposium on The 18th Korea-Japan Cancer Research Workshop, Nasophjaryngeal Carcinoma, Istanbul, 2013. Gifu, 2013. A022. Kasahara, K., Goshima, N., Matsuzaki, F., A032. Kondo, Y.: Mechanistic link between Inagaki, M.: Emarging role of the hepatitis viral infection and induction of aberrant ubiquitin-proteasome pathway in primary cilia DNA methylation in human hepatocyte chimeric assembly. The 25th CDB meeting “Cilia and mice. The 17th Japan-Korea Cancer Research Centrosomes, from Fertilization to Cancer”, Kobe, Workshop, Busan, 2012. 2013. A033. Kondo, Y.: Molecular links between A023. Kasahara, K., Inagaki, M.: Complex microenvironmental signals and epigenetic formation between Plk1 and 14-3-3 gamma is reprogramming processes via long non-coding essential for metapahse to anaphase transition. RNA in glioblastoma. French Japanese Cancer Mini-Symposium on “Stress Signals & Responses”, Meeting, Toulouse, 2013. Abo Akademi University Center of Excellence “Cell stress and Molecular Aging”, Turku, 2012. A034. Kondo, Y.: Polycomb repressive complex 2-mediated epigenetic plasticity contributing to A024. Kasahara, K., Inagaki, M.: Novel mitotic establishment of tissue heterogeneity in signaling crosstalk between PI3K-Akt pahtway and glioblastoma. The 3rd Shanghai International Plk1. Seminar for Center for Brain Repair and Conference of Epigenetics in Development and Rehabilitation, Gothenburg, 2012. Diseases, Shanghai, 2012. A025. Kasahara, K.: Novel mitotic signalling A035. Kondo, Y.: Study of aberrant DNA crosstalk between PI3K-Akt pathway and Plk1. methylation in human hepatocyte chimeric mice. Global COE the 4th International Symposium, International Symposium on Genetic Regulation Nagoya, 2012. and Targeted Therapy of Cancer and 3rd A026. Katsushima, K., Shinjo, K., Natsume, A., Symposium of A3 Foresight Program, Guangzhou, Ohka, F., Fujii, M., Osada, H., Sekido, Y., Kondo, 2012. Y.: Contribution of microRNA-1275 to Claudin11 71

A036. Kondo, Y.: Translational implications of Natsume, A., Katsushima, K., Shinjo, K., Ohka, F., epigenetic changes in human malignancies. 10th Hatanaka, A., Ichimura, N., Kondo, Y.: Epigenetic International Conference of the Asian Clinical plasticity regulated by polycomb repressive Oncology Society, Seoul, 2012. complex 2 in human glioblastoma. Gordon Research Conference, Lucca, 2013. A037. Murakami-Tonami, Y., Kishida, S., Kadomatsu, K.: Inactivation of hSgo1 shows A045. Ohka, F., Natsume, A., Katsushima, K., synthetic phenotype to MYCN amplification. Shinjo, K., Kishida, Y., Motomura, K., Momota, Advanced neuroblastoma research 2012. Toronto, H., Wakabayashi, T., Kondo, Y.: The global DNA 2012. methylation surrogate LINE-1 methylation is correlated with MGMT promoter methylation and A038. Murakami-Tonami, Y.: Inactivation of is a better prognostic factor for glioma. 10th Smc2 shows synergistic lethal response to MYCN International Conference of the Asian Clinical amplification by regulating DNA damage response Oncology Society, Seoul, 2012. genes transcription in neuroblastoma cells. EMBO conference: The DNA damage response in cell A046. Ohka, F., Natsume, A., Ichimura, N., physiology and disease, Greece, 2013. Hatanaka, A., Katsushima, K., Shinjo, K., Zong, H., Kondo,Y.: Loss of p53 and Nf1 and subsequent A039. Murata, T., Noda, C., Kanda, T., Tsurumi, epigenetic alterations in glioblastoma mouse model. T.: Induction of EBV oncogene LMP1 by AP-2 in Gordon Research Conference, Lucca, 2013. NPC cells. 6th International Symposium on Nasopharyngeal Carcinoma, Istanbul, 2013. A047. Ohka, F., Natsume, A., Zong, H., Liu, C., Hatanaka, A., Katsushima, K., Shinjo, K., A040. Murata, T., Tsurumi, T.: Cis- and Wakabayashi, T., Kondo, Y.: Interplay between trans-elements that affect reactivation of genetic loss of p53, Nf1 and histone modifications Epstein-Barr virus from latency. International in tumorigenesis of glioblastoma. The 18th Annual Congress on Oncogenic Herpesviruses and Meeting of the Society for Neuro-Oncology, San Associated Diseases, Philadelphia, 2012. Francisco, 2013. A041. Murata, T., Tsurumi, T.: Modification of A048. Ohka, F.: Loss of p53, Nf1 and subsequent immune/inflammatory system by EBV and its epigenetic alterations during tumor formation of contribution to cancer. 3rd International Glioblastoma. JSPS Sapporo Cancer Epigenetics Symposium on Carcinogenic Spiral and Seminar of the A3 Foresight Program 2013, International Symposium on Tumor Biology in Sapporo, 2013. Kanazawa, Kanazawa, 2013. A049. Oze, I., Matsuo, K., Hosono, S., Ito, H., A042. Nakanishi, H., Saito, T., Kondo, C., Muro, Watanabe, M., Ishioka, K., Ito, S., Tajika, M., K., Kondo, E.: Sensitivity and resistance of Yatabe, Y., Niwa, Y., Yamao, K., Nakamura, S., newly-developed high and low HER2 Tajima, K., Tanaka, H.: The Aldehyde gene-amplified gastric cancer cell lines to Dehydrogenase 2 (ALDH2) Glu504Lys trastuzumab and lapatinib. 10th International Polymorphism Interacts with Alcohol Drinking in Gastric Cancer Congress, Verona, 2013. the Risk of Stomach Cancer. The 4th JCA-AACR A043. Nakatsuka, R., Uemura, Y., Matsuoka, Y., Special Joint Conference: The Latest Advances in Takahashi, M., Iwaki, R., Fujioka, T., Sasaki, Y., Gastric Cancer Research. Urayasu, 2013. Sonoda, Y.: Prospectively isolated PDGFRα and A050. Sakuma, K.: c-Myc and CDX2 mediate Sca-1 double positive dental pulp-derived E-selectin ligand glycan expression in colon cancer mesenchymal stem cell-like cells have different cells undergoing EMT. Global COE the 4th characteristics as compared to PDGFRα and Sca-1 International Symposium, Nagoya, 2012. double positive bone marrow-derived mesenchymal stem cells. ISSCR 10th Annual Meeting, A051. Sekido, Y., Tanaka, I., Fujii, M., Osada, H.: Yokohama, 2012. Hippo signaling cascade alteration in malignant mesothelioma. Keystone Symposia, Monterey, A044. Narita, Y., Murata, T., Kimura, H., 2013. Tsurumi, T.: The Epstein-Barr virus DNA polymerase catalytic subunit BALF5 interacts with A052. Sekido, Y., Tanaka, I., Osada, H., Fujii, M.: Pin1 for efficient productive viral DNA replication. Hippo signaling pathway inactivation in malignant 38th Annual International Herpesvirus Workshop, mesothelioma cells. iMig (international Grand Rapids, 2013. Mesothelioma interest group) 2012, Boston, 2012.

A053. Sekido, Y.: Dysregulation of Hippo in chromosomal instability. Global COE the 4th tumor-suppressive pathway in malignant International Symposium, Nagoya, 2012. mesothelioma. 15th International Association for A063. Tanaka, I., Osada, H., Fujii, M., Sekido, Y.: the Study of Lung Cancer, Sydney, 2013. A LIM protein AJUBA suppresses malignant A054. Sekido, Y.: Molecular Abnormalities and mesothelioma cell proliflation via Hippo signaling Cell Signaling Dysregulation of Malignant Pleural pathway. American Association for Cancer Mesothelioma. The 17th Congress of the Asian Research （ AACR ） Annual Meeting 2013, Pacific Society of Respirology, Hong Kong, 2012. Washington, 2013. A055. Seto, M.: Genomic alterations in malignant A064. Tsurumi, T., Kawashima, D.: Generation of lymphoma and its implication in cancer treatment. Epstein-Barr virus lacking BVLF1 ORF responsible The 38th Annual Meeting of Korean Cancer for late gene transcription. Keystone Symposia on Association, Seoul, 2012. Molecular and Cellular Biology: Advancing A056. Seto, M.: Meet the Professor Sessions· XV. Vaccines in the Genomic Era, Rio de Janeiro, 2013. Malignant lymphoma as a consequence of clonal A065. Tsurumi, T., Kawashima, D.: Nuclear evolution. 12th International Conference on Transport of Epstein-Barr Virus DNA Polymerase Malignant Lymphoma, Cinema Corso, Lugano is dependent on the BMRF1 Polymerase (Switzerland), 2013. Processivity Factor and Molecular Chaperone A057. Shinjo, K., Okamoto, Y., Takeuchi, I., Fujii, Hsp90. The Biology of Molecular Chaperones: M., Osada, H., Usami, N., Ito, H., Hida, T., Sekido, From molecules, organelles and cells to misfolding Y., Kondo, Y.: Integrated analysis of genetic and diseases, Santa Margherita di Pula, 2013. epigenetic alterations reveals CpG island A066. Tsurumi, T., Kawashima, D.: Nuclear methylator phenotype associated with distinct transport of Epstein-Barr virus DNA polymerase is clinical characters of lung adenocarcinoma. AACR dependent on the BMRF1 polymerase processivity Annual Meeting 2012, Chicago, 2012. factor and molecular chaperone Hsp90. 18th World A058. Shinjo, K., Okamoto, Y., Tanaka, Y., Congress on Advances in Oncology and 16th Jean-Pierre Issa, Kondo,Y.: Innate immune system International Symposium on Molecular Medicine, is adequate for induction of DNA methylation after Creta Maris, 2013. hepatitis viral infection in human hepatocyte A067. Tsurumi, T., Sugimoto, A.: Epstein-Barr chimeric mouse . Gordon Research Conference, virus genome packaging factors converge in inner Lucca, 2013. genome storerooms of BMRF1 cores within viral A059. Sugimoto, A., Kimura, H., Tsurumi, T.: replication compartments. The 4th EMBO meeting, Epstein-Barr virus genome packaging factors Nice, 2012. converge at inner part of viral genome storeroom of A068. Tsurumi, T.: Epstein-Barr virus genome the BMRF1 core within viral replication packaging factors converge in inner genome compartment. International Congress on Oncogenic storerooms of BMRF1 cores within viral replication Herpesviruses and Associated Diseases, compartments. SGM spring meeting, Manchester, Philadelphia, 2012. 2013. A060. Tanaka, H.: Cost-effectiveness of smoking A069. Tsurumi, T.: Epstein-Barr virus replication cessationtherapy in Japan. World cancer congress, factory. The 11th Awaji International Forum on Canada, 2012. Infection and Immunity, Awaji, 2012. A061. Tanaka, Hir., Matsuyama, M., Inoko, A., A070. Yamada, E., Demachi-Okamura, A., Kondo, Kondo, E., Kobori, K., Hayashi, Y., Itohara, S., S., Maki, H., Zhang, R., Uemura, Y., Suzuki, S., Izawa, I., Inagaki, M.: Disorder of cytokinesis by Shibata, K., Kikkawa, F., Kuzushima, K.: defect of mitotic vimentin phosphorylation results Identification of novel ovarian cancer-associated in chromosomal instability. The 12th biennial antigens and its epitopes for CTL using an Gordon Conference on Intermediate Filaments, HLA-modified cancer cell line. 9th Joint Lewiston, 2012. Conference of the American Association for Cancer A062. Tanaka, Hir., Matsuyama, M., Inoko, A., Research and the Japanese Cancer Association, Kondo, E., Kobori, K., Hayashi, Y., Itohara, S., Hawaii, 2013. Izawa, I., Inagaki, M.: Disorder of cytokinesis by A071. Yamaguchi, T., Yanagisawa, K., Sugiyama, defect of mitotic vimentin phosphorylation results 73

R., Hosono, Y., Shimada, Y., Arima, C., Kato, S., Tomida, S., Suzuki, M., Osada, H., Takahashi, T.: NKX2-1/TITF1/TTF-1-induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma. AACR annual meeting 2012, Chicago, 2012. A072. Yoshida, N., Karube, K., Utsunomiya, A., Tsukasaki, K., Imaizumi, Y., Taira, N., Uike, N., Umino, A., Arita, K., Suguro, M., Tsuzuki, S., Kinoshita, T., Ohshima, K., Seto, M.: Cell cycle deregulation determines acute transformation in chronic type adult T-cell leukemia/lymphoma. 55th Annual Meeting and Exposition, American Society of Hematology, New Orleans, 2013. A073. Yoshida, N., Umino, A., Liu, F., Arita, K., Karube, K., Tsuzuki, S., Ohshima, K., Seto, M.: Identification of multiple subclones in peripheral T-cell lymphoma, not otherwise specified with genomic aberrations. 54th Annual Meeting and Exposition, American Society of Hematology, Atlanta, 2012. A074. Yusa, A., Masuda, T., Yamamoto, S., Niimi, M., Douke, H., Okochi, M., Toneri, M., Ito, S., Honda, H., Arai, F., Nakanishi, H.: Development of rapid isolation device for circulating tumor cells (CTCs) using size-based filtration method and its application for single cell gene expression analysis. 3rd Annual Meeting World CTC, Boston, 2012.

______Record of Seminars Invited Speakers 2012 Jan. 4 Obuse, C. (Laboratory of Molecular and Cellular Biology, Graduate School of Life Science, Hokkaido University): Crosstalk between constitutive and facultative heterochromatins in the inactive X chromosome.

Jan. 6 Shuda, M. (Cancer Virology Program, University of Pittsburgh Cancer Institute): Merkel cell polyomavirus: identification of the 7th human tumor virus inserted into the genome of Merkel cell carcinoma.

Mar. 30 Trembray, M.L. (Goodman Cancer Research Centre, McGill University): Tyrosine protein phosphatases in cancers: Friends or Foes.

Apr. 23 Tamanoi, F. (Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles): New trends in cancer therapy promoted by chemical biology and nanotechnology.

Sep. 14 Oshima, M. (Division of Genetics, Cancer Research Institute, Kanazawa University): Roles of inflammatory responses in gastric carcinogenesis.

Sep. 28 Sato, Y. (Division of Genetics, Kobe University Graduate School of Medicine): Non-cell-autonomous tumor progression by mitochondrial dysfunction.

Nov. 22 Kurumizaka, H. (Laboratory of Structural Biology, Graduate School of Advanced Science and Engineering, Waseda University): Chromatin structure as the basis of epigenetics.

Nov. 30 Quinlan, R. (Biophysical Sciences Institute, School of Biological and Biomedical Sciences, Durham University): Growth and Form revisited: Applying the D'Arcy Wentworth Thompson principle to the eye lens.

2013 Mar. 1 Ito, K. (Department of Molecular Bone Biology, Graduate School of Biomedical Sciences, Nagasaki University): A view on “the Biology of Cancer” through the prism of the transcription factor RUNX3.

Mar. 14 Enomoto, A. (Department of Pathology, Nagoya University Graduate School of Medicine): Functions of Girdin, a downstream effector of Akt signaling, in tumor progression and development of psychiatric disorders.

Mar. 14 Toyoshima, F. (Department of Cell Biology, Institute for Virus Research, Kyoto University): Signaling network that determines the spindle orientation.

Mar. 19 Ebi, H. (Division of Medical Oncology, Cancer Research Institute, Kanazawa University): Molecularly targeted therapy for lung cancer: comparison with other carcinomas.

Mar. 21 Asai, A. (Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka): Exploring anti-cancer agents with novel mechanisms of action.

Apr. 10 Sawamoto, K. (Department of Developmental & Regenerative Biology, Nagoya City University Graduate School of Medical Sciences): Mechanisms of neural regeneration intrinsic to the brain.

Apr. 16 Takeda, S. (Department of Radiation Genetics, Kyoto University Graduate School of Medicine): Analyzing toxic or pharmacological actions of chemical agents using genetic methods.

Jul. 26 Kitamura, T. (Department of Developmental and Molecular Biology, Albert Einstein College of Medicine): The role of chemokine in macrophage-mediated breast cancer metastasis.

Aug. 9 Sugiura, R. (Laboratory of Molecular Pharmacogenomics, School of Pharmaceutical Sciences, Kinki University): Elucidating the regulatory mechanisms of the MAP kinase signaling pathway and their application to the drug discovery.

Oct. 2 Cheung, E. (Department of Biochemistry, Genome Institute of Singapore): Transcriptional analyses of nuclear hormone signaling in cancer cells.

Oct. 8 Jinushi, M. (Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University): A novel regulatory mechanism for tumor immunity mediated by phagocytosis of apoptotic cells.

Dec. 9 Serfling, E. (Department of Molecular Pathology, Institute of Pathology and Comprehensive Cancer Center, University of Wurzburg): NFATc1 in lymphocytes: Two ‘genes’ in one locus control immunity and cancerogenesis.

Institute Speakers 2012 Jan. 19 Kojima, Y. (Molecular Pathology): Roles of TGF-β and SDF1 in breast cancer microenvironment.

Feb. 16 Kasahara, K. (Biochemistry): Regulation of the mitotic kinase Plk1 by the PI3K/Akt pathway.

May. 17 Nakata, S. (Oncological Pathology): Roles of the cancer stem cell marker gene LGR5 in glioblastoma.

Jun. 21 Matsuo, K. (Epidemiology and Prevention): Correlation between ALDH2 polymorphism and various diseases including cancer: recent updates.

Jul. 30 Saito, S. (Virology): The Epstein-Barr virus deubiquitinase BPLF1 promotes viral DNA replication by blocking TRAF6-mediated activation of the NF-kappaB signaling.

Oct. 17 Karube, K. (Molecular Medicine): Molecular pathology of NK-cell neoplasms.

Nov. 29 Okamura, A. (Immunology): Exploration of novel tumor antigens using an artificial antigen presenting cell system.

2013 Jan. 30 Kajino, R. (Molecular Pathology): TAK1 suppresses enterocyte death and intestinal inflammation

76 by preventing ROS production.

Feb. 14 Goto, H. (Biochemistry): Perspective of kinases regulating cell cycle progression/checkpoint as therapeutic targets for cancer.

Mar. 14 Murakami, Y. (Molecular Oncology): Inactivation of Smc2 shows synergistic lethal response to MYCN amplification by regulating DNA repair genes transcription in neuroblastoma cells.

May. 16 Ito, H. (Epidemiology and Prevention): Cancer prevention strategies based on genetic risks.

Jun. 27 Nakanishi, H. (Oncological Pathology): Development and application of a novel device for capturing circulating tumor cells.

Jun. 28 Matsuo, K. (Epidemiology and Prevention): My fourteen years in Aichi Cancer Center.

Nov. 15 Uemura, Y. (Immunology): Invariant NKT cells as a possible tool for cancer immunotherapy.

Dec. 18 Kanda, T. (Virology): Mechanisms of latent infection of EB virus and its involvement in epithelial carcinogenesis.

______Author index for research reports and publications______Akatsuka, Y. 26, J013, J064, J111, Inagaki, M. 39, 40, 41, 42, J033, J036, J149, J168, A001 J046, J054, J067, J080, Aoki, M. 36, 37, J125, J126, J127 J098, J104, J158, R003, R004, R005, R008, A010, Arita, K. 21, 22, J004, J052, J053, A013, A014, A015, A016, J070, J071, J175, A002, A017, A022, A023, A024, A072, A073 A061, A062 Chihara, D. 6, J008, J009, J010, J055, J112, J159, A003, A004, Inoko, A. 40, 41, J036, J080, J104, A005, A006 J158, R004, A017, A061, Demachi-Okamura, 26, J013, J064, J100, A062 A. J168, A070 Ishiguro, F. 18, J016, J020, J038, Era, S. 39 J039, J084 Fujii, M. 18, 45, J019, J020, J038, Ishioka, K. J078, A049 J039, J075, J084, J102, Islam, T. J040, J041, J144 J150, R001, R002, A007, Ito, H. 6, 7, 8, 9, J006, J008, A008, A026, A027, A051, J009, J010, J018, J019, A052, A057, A063 J022, J031, J032, J040, J041, J043, J044, J057, Fujishita, T. 36, 37, J042 J058, J059, J073, J076, Fujita, M. J064, J100 J078, J079, J080, J082, Fukatsu, A. 18, J020, J150 J091, J093, J094, J115, Fukumoto, K. 7, 9, J021, J043, A009, J116, J120, J127, J138, A018 J139, J144, J145, J151, Furuya, T. 14, J063 J153, J154, J177, J178, A004, A006, A009, A018, Goto, H. 40, 41, J001, J033, J036, A019, A049, A057 J054, J067, J080, J098, J099, J170, R003, R004, R005, A010, A011, A013, Izawa, I. 40, 41, 42, J036, J054, A017 J080, R005, A010, A017, Hatanaka, A. 44, A044, A046, A047 A061, A062 Hayashi, Y. J036, J080, A017, A061, Kakiuchi, T. 22 A062 Kanda, T. 30, 32, 33, 34, J048, J049, He, D. 41 J060, J088, J089, J097, Hiramatsu, K. 26 J124, J146, A020, A021, A039 Hirano, K. J062 Hosono, S. 6, 7, 8, J006, J010, J026, Kannagi, R. 36, J117, J125, J126, J031, J032, J040, J041, J127, J151 J043, J044, J047, J057, Karube, K. 21, 22, J004, J052, J053, J058, J059, J074, J076, J062, J070, J071, J131, J078, J079, J093, J094, J175, A072, A073 J107, J116, J118, J121, J133, J138, J144, J145, Kasahara, K. 39, J054, J067, A010, J177, A018, A019, A049 A022, A023, A024, A025 Kasugai, Y. 22, J004 Ichimura, N. A044, A046 Katayama, M. 21, 22, J004, J052, J156 Iioka, H. 13, 14, J122, J123 Katsushima, K. 44, A026, A027, A028, Inaba, H. 41 A044, A045, A046, A047 Kawakita, D. 6, 8, J057, J058, J059, J076, J081, J116 Kawamoto, E. 39 Kawase, T. J145

Kawashima, D. 32, J048, J060, J088, Matsuyama, M. 40, J036, J067, J080, J089, J097, J124, J146, A017, A061, A062 A064, A065, A066 Morishima, Y. J010, J055, J096, J168, Kobori, K. 40, 41, J080, A061, A062 A001 Kondo, E. 12, 13, 14, 40, J019, J053, Murakami-Tonami, J014, A037, A038 J063, J075, J080, J085, Y. J086, J105, J122, J123, Murata, T. 31, 32, 33, 34, J048, J060, J155, A005, A029, A042, J087, J088, J089, J097, A061, A062 J124, J146, R006, R007, A020, A021, A039, A040, Kondo, S. (IM) J064, J127, A070 A041, A044 Kondo, S. (MP) J127 Kondo, Y. 18, 34, 44, 45, J019, J020, Nakanishi, H. 13, 14, J003, J019, J075, J038, J039, J084, J088, J085, J086, J105, J113, J150, R001, R009, R012, J122, J172, R001, A007, A007, A026, A027, A030, A008, A042, A074 A031, A032, A033, A034, A035, A036, A044, A045, Nakao, M. J093, J094 A046, A047, A057, A058 Nakata, S. 15, J023, J029 Narita, Y. 33, J048, J060, J089, J097, J124, J146, A044 Kumimoto, H. 49 Noda, C. A039 Kuzushima, K. 26, 27, 28, 34, J005, J013, Ohka, F. 44, A026, A027, A044, J015, J035, J049, J064, A045, A046, A047, A048 J083, J090, J100, J110, Okamoto, Y. 45, R009, A057, A058 J111, J149, J168, A001, Osada, H. 18, 45, J016, J019, J020, A070 J038, J039, J084, J143, Li, P. J067, R005 J150, J166, R001, A007, A008, A026, A027, A051, Maki, H. 27, J064, J100, A005, A052, A057, A063, A071 A070 Maseki, S. J075, J105 Oze, I. 6, 7, 8, 9, J027, J031, Matsudaira, Y. J019 J043, J057, J058, J059, Matsuo, K. 6, 7, 8, 9, J006, J008, J066, J076, J078, J079, J009, J010, J011, J012, J093, J102, J103, J114, J017, J018, J021, J022, J115, J116, J128, J142, J025, J028, J031, J032, J153, J177, A018, A019, J034, J037, J040, J041, A049 J043, J044, J045, J047, J050, J051, J056, J057, Saito, K. 12, 13, 14, J063, J122, J058, J059, J061, J065, J123 J066, J068, J072, J073, Saito, S. 33, J060, J088, J124 J076, J077, J078, J079, Saito, T. A042 J081, J082, J091, J093, J094, J095, J096, J108, Sakuma, K. 36, J117, J125, J126, J109, J112, J115, J116, J127, A050 J118, J119, J120, J128, Sato, S. 44, 45 J129, J133, J134, J135, Sato, Y. 32, J146, R010 J136, J137, J138, J139, Sekido, Y. 18, 44, 45, J001, J002, J140, J141, J142, J144, J007, J016, J019, J020, J145, J154, J156, J162, J030, J038, J039, J084, J163, J170, J177, J178, J092, J130, J143, J148, A004, A006, A009, A019, J150, J165, R001, R011, A043, A049 A007, A008, A026, A027, A051, A052, A053, A054, A057, A063

Seto, M. 21, 22, 23, J004, J010, Tanigawa, N. 40 J052, J053, J055, J062, Taniguchi, C. 9, J153 J070, J071, J131, J132, Toneri, M. A074 J147, J157, J160, J161, Tsurumi, T. 30, 31, 32, 33, 34, J048, J164, J167, J173, J174, J049, J060, J087, J088, J175, J176, A002, A038, J089, J097, J124, J146, A055, A056, A072, A073 J151, J169, R006, R007, R010, A020, A021, A039, Shinjo, K. 18, 44, 45, J020, R012, A040, A041, A044, A059, A026, A027, A044, A045, A064, A065, A066, A067, A046, A047, A057, A058 A068, A069 Shiraishi, K. 26 Sueta, A. J018, J040, J082, J144, Tsuzuki, S. 21, 22, 23, J004, J052, J145, J178, A019 J053, J070, J071, J107, Sugimoto, A. 32, J048, J060, J088, J160, J161, J167, J175, J089, J097, J124, J146, A072, A073 A059, A067 Uemura, Y. 27, 28, J064, J099, J100, Tanaka, H. (BC) 40, J080, A061, A062 A012, A043, A070 Tanaka, H. (EP) 6, 7, 8, 9, 14, J010, J024, Wang, Z. J067 J025, J026, J027, J028, Watanabe, M. 8, J031, J032, J040, J041, J031, J032, J034, J040, J057, J058, J059, J078, J041, J043, J044, J056, J079, J093, J094, J116, J057, J058, J059, J068, J138, J144, J177, A019, J075, J076, J078, J079, A049 J080, J085, J086, J093, J094, J101, J105, J106, Yamada, E. A070 J107, J108, J109, J116, Yoshida, N. 21, 22, J004, J052, J053, J129, J138, J144, J145, J070, J071, J131, J173, J152, J153, J154, J162, J174, J175, A072, A073 J177, J178, A009, A018, A019, A049, A060, A061, Yusa, A. A074 A062 Zhang, R. 27, 28, J100, A070

Tanaka, I. 18, J020, J084, J150, R001, A007, A051, A052, A063