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Activation of WD Repeat and High-Mobility Group Box DNA Binding Protein 1 in Pulmonary and Esophageal Carcinogenesis

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Activation of WD Repeat and High-Mobility Group Box DNA Binding Protein 1 in Pulmonary and Esophageal Carcinogenesis Published OnlineFirst December 22, 2009; DOI: 10.1158/1078-0432.CCR-09-1405 Clinical Imaging, Diagnosis, Prognosis Cancer Research Activation of WD Repeat and High-Mobility Group Box DNA Binding Protein 1 in Pulmonary and Esophageal Carcinogenesis Nagato Sato1,2, Junkichi Koinuma1, Masahiro Fujita3, Masao Hosokawa3, Tomoo Ito4, Eiju Tsuchiya5, Satoshi Kondo2, Yusuke Nakamura1, and Yataro Daigo1,6 Abstract Purpose: We attempted to identify novel biomarkers and therapeutic targets for lung and esophageal cancers. Experimental Design: We screened for genes that were overexpressed in a large proportion of lung and esophageal carcinomas using a cDNA microarray representing 27,648 genes or expressed sequence tags. A gene encoding WDHD1, a WD repeat and high-mobility group box DNA binding protein 1, was selected as a candidate. Tumor tissue microarray containing 267 archival non–small cell lung cancers and 283 esophageal squamous cell carcinomas (ESCC) was used to investigate the clinicopathologic significance of WDHD1 expression. The role of WDHD1 in cancer cell growth and/or survival was examined by small interfering RNA experiments and cell growth assays. The mechanism of WDHD1 activation through its phosphorylation in cancer cells was examined by immunoprecipitation and kinase assays. Results: Positive WDHD1 immunostaining was associated with a poor prognosis for patients with non–small cell lung cancer (P = 0.0403) as well as ESCC (P = 0.0426). Multivariate analysis indicated it to be an independent prognostic factor for ESCC (P = 0.0104). Suppression of WDHD1 expression with small interfering RNAs effectively suppressed lung and esophageal cancer cell growth. In addition, induc- tion of the exogenous expression of WDHD1 promoted the growth of mammalian cells. AKT1 kinase seemed to phosphorylate and stabilize the WDHD1 protein in cancer cells. Conclusions: WDHD1 expression is likely to play an important role in lung and esophageal carcino- genesis as a cell cycle regulator and a downstream molecule in the phosphoinositide 3-kinase/AKT pathway, and that WDHD1 is a candidate biomarker and a promising therapeutic target for cancer. Clin Cancer Res; 16(1); 226–39. ©2010 AACR. Aerodigestive tract cancer (including carcinomas of lung, them consists of the squamous cell carcinoma. In spite of esophagus, oral cavity, pharynx, and larynx) accounts for the use of modern surgical techniques combined with var- one third of all cancer deaths in the United States and is ious treatment modalities, such as radiotherapy and che- the most common cancer in some parts of the world (1). motherapy, lung cancer and esophageal squamous cell Lung and esophageal cancers are the two major thoracic carcinoma (ESCC) are known to have the worst prognosis cancers that share common clinicopathologic characteris- of all malignant tumors; 5-year survival rates for lung can- tics: (a) embryologically, both of them are derived from cer patients including all disease stages still remain as low endoblast; (b) epidemiologically, there is a risk factor such as 15% and those for ESCC patients are much the same at as smoking; and (c) pathologically, a certain proportion of 16% (2, 3). A better understanding of the molecular basis of cancer has led to novel targeted strategies that inhibit specific key molecules in tumor growth, however currently Authors' Affiliations: 1Laboratory of Molecular Medicine, Human Genome available new targeted therapies are expected to improve Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; 2Department of Surgical Oncology, Hokkaido University Graduate School the prognosis of a small number of patients (4, 5). There- of Medicine; 3Keiyukai Sapporo Hospital; and 4Department of Surgical fore, novel strategies such as the development of molecu- Pathology, Hokkaido University, Sapporo, Japan; 5Kanagawa Cancer lar-targeted agents and cancer vaccines, which target Center Research Institute, Yokohama, Japan; and 6Department of Medical Oncology, Shiga University of Medical Science, Otsu, Japan molecules essential for the growth/survival of cancer cells, are eagerly awaited. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). We have been attempting to isolate potential molecu- Corresponding Author: Yataro Daigo, Institute of Medical Science, The Univer- lar targets for diagnosis and/or treatment of lung cancer sity of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639 Japan. Phone: and ESCC by analyzing genome-wide expression profiles 81-3-5449-5457; Fax: 81-3-5449-5406; E-mail: [email protected]. of 101 lung cancer and 19 ESCC tissue samples on a doi: 10.1158/1078-0432.CCR-09-1405 cDNA microarray containing 27,648 genes or expressed © 2010 American Association for Cancer Research. sequence tags (6–12). To verify the biological and clinical 226 Clin Cancer Res; 16(1) January 1, 2010 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst December 22, 2009; DOI: 10.1158/1078-0432.CCR-09-1405 WDHD1 in Pulmonary and Esophageal Carcinogenesis Materials and Methods Translational Relevance Cell lines and tissue samples. The human lung cancer cell Because there is a correlation between WDHD1 ex- lines used in this study were as follows: lung adenocarcino- pression and poor prognosis for patients with lung and mas (ADC) NCI-H1781, NCI-H1373, LC319, A549, and esophageal carcinomas, and multivariate analysis indi- PC14; lung squamous cell carcinomas (SCC) SK-MES-1, cated it to be an independent prognostic factor for NCI-H2170, NCI-H520, NCI-H1703, and LU61; a lung esophageal carcinomas, WDHD1 positivity in resected large-cell carcinoma LX1; and small-cell lung cancers specimens could be an index that provides informa- (SCLC) SBC-3, SBC-5, DMS273, and DMS114 (Supple- tion useful to physicians in applying adjuvant therapy mentary Table S1). The human esophageal carcinoma cell and intensive follow-up to the cancer patients who are lines used in this study were as follows: 10 SCC cell lines likely to suffer a relapse. Because WDHD1 should (TE1, TE2, TE3, TE4, TE5, TE6, TE8, TE9, TE10, and TE11) properly be classified as a typical cancer testis antigen and one ADC cell line (TE7; ref. 42). All cells were grown in and is likely to play an important role as a key compo- monolayer in appropriate medium supplemented with nent of the phosphoinositide 3-kinase/AKT pathway in 10% FCS and maintained at 37°C in humidified air with cancer proliferation, the selective inhibition of 5% CO2. Human small airway epithelial cells (SAEC) used WDHD1 expression and/or the targeting of enzymatic as a normal control were grown in optimized medium interaction between AKT1 and WDHD1 by small mol- (small airway growth medium) from Cambrex Bioscience, ecule compounds could be a promising therapeutic Inc. Primary non-SCLC (NSCLC) and ESCC tissue samples strategy that is expected to have a powerful biological as well as their corresponding normal tissues adjacent to re- effect on cancer with a minimal risk of adverse events. section margins from patients having no anticancer treat- ment before tumor resection had been obtained earlier with informed consent (7, 11, 12, 15). All tumors were significance of the gene products, we have established a staged on the basis of the pathologic tumor-node-metasta- screening system by combining the tumor tissue microar- sis classification of the International Union Against Cancer ray analysis of clinical lung and ESCC with RNA interfer- (43). Formalin-fixed primary lung tumors and adjacent ence technique and cell growth assays (13–37). In the normal lung tissue samples used for immunostaining on course of these systematic studies, we found that WD re- tissue microarrays had been obtained from 267 patients un- peat and high-mobility group box DNA binding protein dergoing curative surgery at Hokkaido University and its af- 1(WDHD1; alias acidic nucleoplasmic DNA-binding pro- filiated hospitals (Sapporo, Japan; please see tein, AND-1) was overexpressed in the great majority of Supplementary Table S2A). A total of 283 formalin-fixed lung cancers and ESCCs. primary ESCCs and adjacent normal esophageal tissue sam- WDHD1 is a human homologue of Ctf4 in Saccharomyces ples near to resection margins had also been obtained from cerevesiae, which was originally identified by screening for patients undergoing curative surgery at Hokkaido Universi- mutant genes affecting chromosome transmission fidelity ty Hospital and Keiyukai Sapporo Hospital (Sapporo, Ja- (38). Later studies indicate that Ctf4 is required for sister pan; Supplementary Table S2B). To be eligible for this chromatid cohesion and interacts with DNA polymerase study, tumor samples were selected from patients who ful- α in yeasts (39). Mcl1, a homologue of CTF4 in Schizosac- filled all of the following criteria: (a) patients suffered pri- charomyces pombe, is essential for the viability, maintenance mary NSCLC or ESCC with histologically confirmed stage of genome integrity, and regulation of telomere replication (only pT1 to pT3,pN0 to pN2, and pM0); (b) patients under- in fission yeast (40). Mcl1/Ctf4 is functionally related with went curative surgery, but did not receive any preoperative molecules involved in lagging strand DNA synthesis such as treatment; (c) among them, NSCLC patients with positive Rad2, Dna2, and Fen1 that plays a role in processing Oka- lymph node metastasis (pN1,pN2) were treated with plati- zaki fragments and physically interacts with DNA polymer- num-based adjuvant chemotherapies after surgery, and ase α to promote the chromatin association of DNA ESCC patients with pN positive were treated with adjuvant polymerase α (40), but its exact role in DNA replication chemotherapy using both platinum and 5-fluorouracil after has not yet been defined. Recently, it has been shown that surgery, whereas patients with pN0 did not receive adjuvant WDHD1 could interact with Mcm10 and is required for the chemotherapies; and (d) patients whose clinical follow-up proper loading of DNA polymerase α and replication initi- data were available.
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