DOCSLIB.ORG

ORIGINAL ARTICLE Prognostic Value of Chromosome 1Q21 Gain

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
ORIGINAL ARTICLE Prognostic Value of Chromosome 1Q21 Gain Leukemia (2006) 20, 2034–2040 & 2006 Nature Publishing Group All rights reserved 0887-6924/06 $30.00 www.nature.com/leu ORIGINAL ARTICLE Prognostic value of chromosome 1q21 gain by fluorescent in situ hybridization and increase CKS1B expression in myeloma R Fonseca1, SA Van Wier1, WJ Chng1, R Ketterling2, MQ Lacy3, A Dispenzieri3, PL Bergsagel1, SV Rajkumar3, PR Greipp3, MR Litzow3, T Price-Troska3, KJ Henderson3, GJ Ahmann1 and MA Gertz3 1Division of Hematology and Oncology, Mayo Clinic Comprehensive Cancer Center, Scottsdale, AZ, USA; 2Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA and 3Division of Hematology, Mayo Clinic, Rochester, MN, USA A specific role for increased level of expression of CKS1B,asa including deletions and mutations of p53, and mutations of ras consequence of chromosome 1q21 copy number gain, has have been associated with disease progression, but only for a been postulated as both pathogenic, as well as a powerful small fraction of cases, and with yet to be proven pathogenic clinical prognostic factor in multiple myeloma (MM). The 1 purpose of this study is to determine the clinical associations consequences. and prognostic impact of copy number gain at chromosome Recently the group from the University of Arkansas (UAMS) 1q21 (with a bacteria artificial chromosome clone containing identified strong prognostic associations with an increased level CKS1B) and CKS1B gene level of expression in MM. We studied of gene expression of a cell cycle associated gene, CKS1B, the chromosome region 1q21 for copy number change in a located on chromosome 1q21.9,10 CKS1B favors cell cycle cohort of myeloma patients treated by high-dose therapy with progression by promoting degradation of p27 with release of the stem-cell rescue (HDT) (n ¼ 159). A separate cohort of patients, 11,12 treated by HDT was studied for CKS1B messenger RNA cyclin dependent kinases and entry into mitosis. This expression by gene expression profiling (n ¼ 67). 1q21 gain increased level of expression is associated with copy number was then correlated with clinical parameters and survival. Gain gain of chromosome 1 at band q21 in a subset of patients. of 1q21 copy number was detected in about a third of MM and Subsequently, the same group showed that 1q21 copy gain by was associated with more proliferative disease and poor-risk Fluorescent in situ hybridization (FISH) using a bacteria artificial cytogenetic categories such as t(4;14), and chromosome 13 chromosome (BAC) probe for CKS1B was also an important deletion. Both 1q21 gain and increase gene expression level 13 were significantly associated with reduced survival. However, prognostic factor in MM patients entered into total therapy II. neither is an independent prognostic marker in MM on multi- Previously comparative genomic hybridization studies have variate Cox proportional hazard analysis. shown that gains of chromosome 1q consistently involving the Leukemia (2006) 20, 2034–2040. doi:10.1038/sj.leu.2404403; 1q21 region is one of the most common genetic abnormalities in published online 5 October 2006 MM.14–16 Gain of 1q21 can occur as isochromosomes, Keywords: multiple myeloma; stem cell transplantation; gene 17,18 amplification; CKS1B; chromosome 1 duplications or jumping translocations in MM. Many of these chromosome changes are structural and do not involve copy number changes. However, the association of 1q21 copy gain and expression with proliferation and recurrent genetic abnormalities, and their relative impact on survival have not been clearly established. In Introduction this study, we assessed gain of chromosome 1q21 by FISH and increase CKS1B gene expression by gene expression profiling Molecular cytogenetic studies have revealed that, to a great (GEP), their relationship, prognostic impact and clinical and extent, the clinical heterogeneity of multiple myeloma (MM) is biologic correlations. dictated by the underlying genetic and cytogenetic aberrations present in the clonal plasma cells (PCs). This greater under- standing has defined several molecular subtypes of myeloma Patients and methods characterized primarily by the presence of specific chromosome translocations and associated chromosome ploidy changes.1–3 Patient cohorts This characterization is also associated, and ratified, by the Group 1: Mayo Clinic patients treated with HDT studied existence of specific transcription patterns that emerge from by FISH. We studied a cohort of 159 patients treated at the 4,5 these cytogenetically defined categories. It is also clear that Mayo Clinic that had been treated with melphalan-based high- these major cytogenetic categories are already present in the dose therapy (HDT). Patients were treated with melphalan at 6–8 early stages of the disease (i.e., MGUS), and that additional 200 mg/m2 (n ¼ 63) or melphalan at 140 mg/m2 plus total body genetic insults must participate in the progression to the more irradiation (n ¼ 83), and other conditioning regimens in 13. Of aggressive forms of the disease. Several candidate aberrations these patients 89 (56%) had been transplanted at the time of relapse. Of the 159 patients 114 have died. Median and Correspondence: Dr R Fonseca, Division of Hematology and minimum follow-up of the 45 survivors is 55 and 43 months, Oncology, Mayo Clinic Comprehensive Cancer Center, Johnson respectively. Research Building 356, Mayo Clinic, 13400 E Shea Boulevard, In all cases studied a research bone marrow (BM) sample had Scottsdale, AZ 85259, USA. E-mail: [email protected] been obtained before HDT. All patients gave written informed Received 11 July 2006; accepted 17 August 2006; published online consent for the collection and long-term storage of additional 5 October 2006 cells at the time of the BM examination including separate Chromosome 1q21 copy change and prognosis in myeloma R Fonseca et al 2035 authorization for genetic studies and separate consent for review a matrix to define the actual proportion of cells exhibiting a of their charts in accord with both federal regulations and possible amplification or copy gain pattern, and determine a Health Insurance Portability and Accountability Act (HIPAA) final ratio (Supplementary Figure 1). A ratio greater than 1 guidelines. The consent was approved by the Institutional represents copy gain of 1q21. This strategy will allow the Review Board of the Mayo Clinic College of Medicine. Cytospin assessment of the effect of 1q21 gain independent of ploidy slides were made in all cases and the remaining sample was changes. The second strategy is similar to that used by purified using CD138 þ magnetic beads when possible and Hanamura et al.,13 where the absolute copy of 1q21 is counted. stored in liquid nitrogen for future use. All patients in whom We considered patients who have three or more signals in more available samples were obtained were used in this analysis. than 20% of cells counted as having gain of chromosome 1q21. One hundred cIg-positive cells were counted. Group 2: Mayo Clinic patients studied by GEP. Gene expression analysis was performed on CD138 þ selected PCs from pretreatment BM samples of 67 newly diagnosed MM GEP patients using the Affymetrix U133A chip (Affymetrix, Santa Gene expression analysis was performed on CD138 þ cells Clara, CA, USA). This group of patients was subsequently treated using the Affymetrix U133A chip (Affymetrix, Santa Clara, CA, with various forms of therapy including HDT and stem cell USA). RNA isolation, purification and microarray hybridization rescue in 63% (none of these patients are in group 1), has been reported previously.23 Gene expression intensity melphalan-based oral chemotherapy in 21%, dexamethasone- values were log transformed, normalized to the median and based chemotherapy in 13% and novel agents in 3%. analyzed using GeneSpring 7 (Agilent Technologies, Palo Alto, CA, USA). Group 3: UAMS patients treated with HDT (Total Therapy II). These are newly diagnosed patients entered into Total Therapy II studies. These patients have FISH analysis for Statistics 1q21 copy number using the same probe as that used in our To describe the prevalence of abnormalities we used simple þ study, as well as GEP performed on CD138 selected PCs from descriptive statistics. The Wilcoxon rank sum test was used to pretreatment BMs using the Affymetrix U133plus chip. The FISH compare the difference in PC labeling index (PCLI) between 13,19 and GEP of these patients have been published. For our patients with and without 1q21 copy change. Correlation analysis we utilized a subset of patients (n ¼ 248) with both FISH between the level of CKS1B gene expression and the PCLI was and GEP results available (These data are available from the NIH assessed using the Pearson’s correlation coefficient. The Gene Expression Omnibus, http://www.ncbi.nlm.nih.gov/geo/, relationship between 1q21 copy change and CKS1B gene under accession number GSE2658). These patients were expression and cytogenetic categories was assessed by the w2 assigned Translocations and Cyclin (TC) class and a gene test. Two-tailed p-values were reported with the significance expression-based proliferation index (PI) based on published level set at 0.05. Survival (overall and progression free) 4 methods. probabilities were determined using the methods of Kaplan– Meier. Cox proportional hazards models were used to assess the association of several prognostic factors with survival. Methods FISH. The cytoplasmic immunoglobulin light chain (cIg-FISH) technique20 that combined the interphase FISH strategy with fluorescent detection of cIg was used. For the detection of the Results common chromosome abnormalities (t(11;14)(q13;q32), t(4;14)(p16;q32), þ 14q32, chromosome 13 abnormalities Clinical features of patients studied for DNA copy gain (D13) and À17p13), we used the same probes and conditions A total of 159 patients, in whom we had stored research samples published previously by us.21 and had been treated with HDT and stem cell transplant To score for 1q21 copy gain by FISH we used a BAC RPCI between January 1990 and January 2001, were studied.
Load more

Recommended publications
  • Supplementary Data
    SUPPLEMENTARY DATA A cyclin D1-dependent transcriptional program predicts clinical outcome in mantle cell lymphoma Santiago Demajo et al. 1 SUPPLEMENTARY DATA INDEX Supplementary Methods p. 3 Supplementary References p. 8 Supplementary Tables (S1 to S5) p. 9 Supplementary Figures (S1 to S15) p. 17 2 SUPPLEMENTARY METHODS Western blot, immunoprecipitation, and qRT-PCR Western blot (WB) analysis was performed as previously described (1), using cyclin D1 (Santa Cruz Biotechnology, sc-753, RRID:AB_2070433) and tubulin (Sigma-Aldrich, T5168, RRID:AB_477579) antibodies. Co-immunoprecipitation assays were performed as described before (2), using cyclin D1 antibody (Santa Cruz Biotechnology, sc-8396, RRID:AB_627344) or control IgG (Santa Cruz Biotechnology, sc-2025, RRID:AB_737182) followed by protein G- magnetic beads (Invitrogen) incubation and elution with Glycine 100mM pH=2.5. Co-IP experiments were performed within five weeks after cell thawing. Cyclin D1 (Santa Cruz Biotechnology, sc-753), E2F4 (Bethyl, A302-134A, RRID:AB_1720353), FOXM1 (Santa Cruz Biotechnology, sc-502, RRID:AB_631523), and CBP (Santa Cruz Biotechnology, sc-7300, RRID:AB_626817) antibodies were used for WB detection. In figure 1A and supplementary figure S2A, the same blot was probed with cyclin D1 and tubulin antibodies by cutting the membrane. In figure 2H, cyclin D1 and CBP blots correspond to the same membrane while E2F4 and FOXM1 blots correspond to an independent membrane. Image acquisition was performed with ImageQuant LAS 4000 mini (GE Healthcare). Image processing and quantification were performed with Multi Gauge software (Fujifilm). For qRT-PCR analysis, cDNA was generated from 1 µg RNA with qScript cDNA Synthesis kit (Quantabio). qRT–PCR reaction was performed using SYBR green (Roche).
    [Show full text]
  • Aneuploidy: Using Genetic Instability to Preserve a Haploid Genome?
    Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Science (Cancer Biology) Aneuploidy: Using genetic instability to preserve a haploid genome? Submitted by: Ramona Ramdath In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Science Examination Committee Signature/Date Major Advisor: David Allison, M.D., Ph.D. Academic James Trempe, Ph.D. Advisory Committee: David Giovanucci, Ph.D. Randall Ruch, Ph.D. Ronald Mellgren, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: April 10, 2009 Aneuploidy: Using genetic instability to preserve a haploid genome? Ramona Ramdath University of Toledo, Health Science Campus 2009 Dedication I dedicate this dissertation to my grandfather who died of lung cancer two years ago, but who always instilled in us the value and importance of education. And to my mom and sister, both of whom have been pillars of support and stimulating conversations. To my sister, Rehanna, especially- I hope this inspires you to achieve all that you want to in life, academically and otherwise. ii Acknowledgements As we go through these academic journeys, there are so many along the way that make an impact not only on our work, but on our lives as well, and I would like to say a heartfelt thank you to all of those people: My Committee members- Dr. James Trempe, Dr. David Giovanucchi, Dr. Ronald Mellgren and Dr. Randall Ruch for their guidance, suggestions, support and confidence in me. My major advisor- Dr. David Allison, for his constructive criticism and positive reinforcement.
    [Show full text]
  • Stem Cells® Original Article
    ® Stem Cells Original Article Properties of Pluripotent Human Embryonic Stem Cells BG01 and BG02 XIANMIN ZENG,a TAKUMI MIURA,b YONGQUAN LUO,b BHASKAR BHATTACHARYA,c BRIAN CONDIE,d JIA CHEN,a IRENE GINIS,b IAN LYONS,d JOSEF MEJIDO,c RAJ K. PURI,c MAHENDRA S. RAO,b WILLIAM J. FREEDa aCellular Neurobiology Research Branch, National Institute on Drug Abuse, Department of Health and Human Services (DHHS), Baltimore, Maryland, USA; bLaboratory of Neuroscience, National Institute of Aging, DHHS, Baltimore, Maryland, USA; cLaboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA; dBresaGen Inc., Athens, Georgia, USA Key Words. Embryonic stem cells · Differentiation · Microarray ABSTRACT Human ES (hES) cell lines have only recently been compared with pooled human RNA. Ninety-two of these generated, and differences between human and mouse genes were also highly expressed in four other hES lines ES cells have been identified. In this manuscript we (TE05, GE01, GE09, and pooled samples derived from describe the properties of two human ES cell lines, GE01, GE09, and GE07). Included in the list are genes BG01 and BG02. By immunocytochemistry and reverse involved in cell signaling and development, metabolism, transcription polymerase chain reaction, undifferenti- transcription regulation, and many hypothetical pro- ated cells expressed markers that are characteristic of teins. Two focused arrays designed to examine tran- ES cells, including SSEA-3, SSEA-4, TRA-1-60, TRA-1- scripts associated with stem cells and with the 81, and OCT-3/4. Both cell lines were readily main- transforming growth factor-β superfamily were tained in an undifferentiated state and could employed to examine differentially expressed genes.
    [Show full text]
  • A Bacterial Protein Targets the BAHD1 Chromatin Complex to Stimulate Type III Interferon Response
    A bacterial protein targets the BAHD1 chromatin complex to stimulate type III interferon response Alice Lebreton, Goran Lakisic, Viviana Job, Lauriane Fritsch, To Nam Tham, Ana Camejo, Pierre-Jean Matteï, Béatrice Regnault, Marie-Anne Nahori, Didier Cabanes, et al. To cite this version: Alice Lebreton, Goran Lakisic, Viviana Job, Lauriane Fritsch, To Nam Tham, et al.. A bacterial protein targets the BAHD1 chromatin complex to stimulate type III interferon response. Science, American Association for the Advancement of Science, 2011, 331 (6022), pp.1319-21. 10.1126/sci- ence.1200120. cea-00819299 HAL Id: cea-00819299 https://hal-cea.archives-ouvertes.fr/cea-00819299 Submitted on 26 Jul 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Lebreton et al. Science 2011 doi:10.1126/science.1200120 A Bacterial Protein Targets the BAHD1 Chromatin Complex to Stimulate Type III Interferon Response Alice Lebreton1,2,3, Goran Lakisic4, Viviana Job5, Lauriane Fritsch6, To Nam Tham1,2,3, Ana Camejo7, Pierre-Jean Matteï5, Béatrice Regnault8, Marie-Anne Nahori1,2,3, Didier Cabanes7, Alexis Gautreau4, Slimane Ait-Si-Ali6, Andréa Dessen5, Pascale Cossart1,2,3* and Hélène Bierne1,2,3* 1.
    [Show full text]
  • Identification of Gastric Cancer–Related Genes Using a Cdna Microarray Containing Novel Expressed Sequence Tags Expressed in Gastric Cancer Cells
    Vol. 11, 473–482, January 15, 2005 Clinical Cancer Research 473 Identification of Gastric Cancer–Related Genes Using a cDNA Microarray Containing Novel Expressed Sequence Tags Expressed in Gastric Cancer Cells Jeong-Min Kim,1,5 Ho-Yong Sohn,4 overexpressed in z68% of tissues and the MT2A gene Sun Young Yoon,1 Jung-Hwa Oh,1 Jin Ok Yang,1 was down-expressed in 72% of the tissues. Western blotting and immunohistochemical analyses for CDC20 and SKB1 Joo Heon Kim,2 Kyu Sang Song,3 Seung-Moo Rho,2 1 1 5 showed overexpression and localization changes of the Hyan Sook Yoo, Yong Sung Kim, Jong-Guk Kim, corresponding protein in human gastric cancer tissues. 1 and Nam-Soon Kim Conclusions: Novel genes that are related to human 1Genome Research Center, Korea Research Institute of Bioscience and gastric cancer were identified using cDNA microarray Biotechnology; 2Department of Pathology, Eulji University School of 3 developed in our laboratory. In particular, CDC20 and Medicine; and Department of Pathology, College of Medicine, MT2A represent a potential biomarker of human gastric Chungnam National University, Daejeon, Korea; 4Department of Food and Nutrition, Andong National University, Andong, Korea; and cancer. These newly identified genes should provide a 5Department of Microbiology, College of Natural Sciences, Kyungpook valuable resource for understanding the molecular mecha- National University, Daegu, Korea nism associated with tumorigenesis of gastric carcinogenesis and for the discovery of potential diagnostic markers of gastric cancer. ABSTRACT Purpose: Gastric cancer is one of the most frequently INTRODUCTION diagnosed malignancies in the world, especially in Korea and Japan.
    [Show full text]
  • Downregulation of SNRPG Induces Cell Cycle Arrest and Sensitizes Human Glioblastoma Cells to Temozolomide by Targeting Myc Through a P53-Dependent Signaling Pathway
    Cancer Biol Med 2020. doi: 10.20892/j.issn.2095-3941.2019.0164 ORIGINAL ARTICLE Downregulation of SNRPG induces cell cycle arrest and sensitizes human glioblastoma cells to temozolomide by targeting Myc through a p53-dependent signaling pathway Yulong Lan1,2*, Jiacheng Lou2*, Jiliang Hu1, Zhikuan Yu1, Wen Lyu1, Bo Zhang1,2 1Department of Neurosurgery, Shenzhen People’s Hospital, Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518020, China;2 Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China ABSTRACT Objective: Temozolomide (TMZ) is commonly used for glioblastoma multiforme (GBM) chemotherapy. However, drug resistance limits its therapeutic effect in GBM treatment. RNA-binding proteins (RBPs) have vital roles in posttranscriptional events. While disturbance of RBP-RNA network activity is potentially associated with cancer development, the precise mechanisms are not fully known. The SNRPG gene, encoding small nuclear ribonucleoprotein polypeptide G, was recently found to be related to cancer incidence, but its exact function has yet to be elucidated. Methods: SNRPG knockdown was achieved via short hairpin RNAs. Gene expression profiling and Western blot analyses were used to identify potential glioma cell growth signaling pathways affected by SNRPG. Xenograft tumors were examined to determine the carcinogenic effects of SNRPG on glioma tissues. Results: The SNRPG-mediated inhibitory effect on glioma cells might be due to the targeted prevention of Myc and p53. In addition, the effects of SNRPG loss on p53 levels and cell cycle progression were found to be Myc-dependent. Furthermore, SNRPG was increased in TMZ-resistant GBM cells, and downregulation of SNRPG potentially sensitized resistant cells to TMZ, suggesting that SNRPG deficiency decreases the chemoresistance of GBM cells to TMZ via the p53 signaling pathway.
    [Show full text]
  • Cell-Cycle Regulator Cks1 Promotes Hepatocellular Carcinoma by Supporting NF-Kb–Dependent Expression of Interleukin-8
    Published OnlineFirst September 14, 2011; DOI: 10.1158/0008-5472.CAN-10-4356 Cancer Tumor and Stem Cell Biology Research Cell-Cycle Regulator Cks1 Promotes Hepatocellular Carcinoma by Supporting NF-kB–Dependent Expression of Interleukin-8 Eun-Kyoung Lee1,2, Dae-Ghon Kim3, Jang-Seong Kim1, and Yeup Yoon1 Abstract The cell-cycle regulator Cks1 has recently been implicated in Skp2-mediated ubiquitination of the tumor suppressor protein p27. In this article, we report that Cks1 exerts a Skp2-independent regulation of NF-kB that promotes interleukin-8 (IL-8) expression, which is critical to hepatocellular carcinoma (HCC) growth. Cks1 was upregulated frequently in human HCC tissues and cell lines. Cks1 knockdown in HCC cells elevated p27 levels and decreased tumorigenicity in a manner that was also associated with a strong downregulation of IL-8 expression. IL-8 downregulation was not phenocopied by either RNAi-mediated knockdown of Skp2 or ectopic over- expression of p27. However, attenuation of IL-8 expression itself was sufficient to blunt HCC growth. Mechanistic investigations revealed that IL-8 was controlled at a transcriptional level by Cks1 targeting of the NF-kB regulator IkBa, which led to NF-kB activation and IL-8 expression, through a p27-independent regulation of IkB kinase complex components. Collectively, our findings support the hypothesis that Cks1 supports hepatocarcinogenesis by NF-kB–mediated regulation of IL-8 expression, broadening the function of Cks1 in cancer beyond its role as a Skp2 cofactor in p27 ubiquitination. Cancer Res; 71(21); 1–9. Ó2011 AACR. Introduction was identified as an essential cofactor of Skp2 in the Skp2- containing Skp1-Cullin1-F-box ubiquitin ligase complex Hepatocellular carcinoma (HCC) is the third most common (SCFSkp2)–mediated ubiquitination of the tumor suppressor cause of cancer-related deaths worldwide (1).
    [Show full text]
  • Chromatin Conformation Links Distal Target Genes to CKD Loci
    BASIC RESEARCH www.jasn.org Chromatin Conformation Links Distal Target Genes to CKD Loci Maarten M. Brandt,1 Claartje A. Meddens,2,3 Laura Louzao-Martinez,4 Noortje A.M. van den Dungen,5,6 Nico R. Lansu,2,3,6 Edward E.S. Nieuwenhuis,2 Dirk J. Duncker,1 Marianne C. Verhaar,4 Jaap A. Joles,4 Michal Mokry,2,3,6 and Caroline Cheng1,4 1Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands; and 2Department of Pediatrics, Wilhelmina Children’s Hospital, 3Regenerative Medicine Center Utrecht, Department of Pediatrics, 4Department of Nephrology and Hypertension, Division of Internal Medicine and Dermatology, 5Department of Cardiology, Division Heart and Lungs, and 6Epigenomics Facility, Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands ABSTRACT Genome-wide association studies (GWASs) have identified many genetic risk factors for CKD. However, linking common variants to genes that are causal for CKD etiology remains challenging. By adapting self-transcribing active regulatory region sequencing, we evaluated the effect of genetic variation on DNA regulatory elements (DREs). Variants in linkage with the CKD-associated single-nucleotide polymorphism rs11959928 were shown to affect DRE function, illustrating that genes regulated by DREs colocalizing with CKD-associated variation can be dysregulated and therefore, considered as CKD candidate genes. To identify target genes of these DREs, we used circular chro- mosome conformation capture (4C) sequencing on glomerular endothelial cells and renal tubular epithelial cells. Our 4C analyses revealed interactions of CKD-associated susceptibility regions with the transcriptional start sites of 304 target genes. Overlap with multiple databases confirmed that many of these target genes are involved in kidney homeostasis.
    [Show full text]
  • Skp2 Is an Independent Prognosticator of Gallbladder
    Modern Pathology (2007) 20, 497–507 & 2007 USCAP, Inc All rights reserved 0893-3952/07 $30.00 www.modernpathology.org Skp2 is an independent prognosticator of gallbladder carcinoma among p27Kip1-interacting cell cycle regulators: an immunohistochemical study of 62 cases by tissue microarray Shau-Hsuan Li1, Chien-Feng Li2, Ming-Tse Sung3, Hock-Liew Eng3, Ching-Yeh Hsiung4, Wen-Wei Huang5, Ching-Nan Lin2, Shih-Chen Yu3 and Hsuan-Ying Huang3 1Division of Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Department of Pathology, Chi-Mei Foundation Medical Center, Tainan, Taiwan; 3Department of Pathology, Chang Gung Memorial Hospital- Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan; 4Department of Radiation Oncology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan and 5Department of Family Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan Despite improvement in surgical techniques, prognosis of gallbladder carcinoma remains poor. It is desirable to identify prognostic biomarkers to aid in the development of targeted therapeutic strategies. Two SCFSkp2 ubiquitin ligase-related proteins, Skp2 and cyclin-dependent kinase subunit 1 (Cks1), are involved in post- transcriptional degradation of p27Kip1 tumor suppressor, which inhibits both cdk2/cyclin E and cdk2/cyclin A complexes and thus prevents transition to the S phase. However, the prognostic utility of p27Kip1-interacting cell cycle regulators has not been systematically assessed in gallbladder carcinoma. Immunohistochemistry was performed for p27Kip1, Skp2, Cks1, cyclin E, cyclin A, and Ki-67 in tissue microarrays of 62 gallbladder carcinomas with follow-up.
    [Show full text]
  • Complex-Based Analysis of Dysregulated Cellular Processes In
    Complex-based analysis of dysregulated cellular processes in cancer Sriganesh Srihari∗1, Piyush B. Madhamshettiwar1, Sarah Song1, Chao Liu1, Peter T. Simpson2, Kum Kum Khanna3, and Mark A. Ragan∗1 1Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia. 2The University of Queensland Centre for Clinical Research, Brisbane, Queensland 4006, Australia. 3QIMR-Berghofer Institute of Medical Research, Brisbane, Queensland 4006, Australia. Email: SS1∗– [email protected]; PBM – [email protected]; SS2 – [email protected]; CL – [email protected]; PTS – [email protected]; KKK – [email protected]; MAR∗– [email protected]; ∗Corresponding author Abstract Background: Differential expression analysis of (individual) genes is often used to study their roles in diseases. However, diseases such as cancer are a result of the combined effect of multiple genes. Gene products such as proteins seldom act in isolation, but instead constitute stable multi-protein complexes performing dedicated functions. Therefore, complexes aggregate the effect of individual genes (proteins) and can be used to gain a better understanding of cancer mechanisms. Here, we observe that complexes show considerable changes in their expression, in turn directed by the concerted action of transcription factors (TFs), across cancer conditions. arXiv:1408.1177v1 [q-bio.MN] 6 Aug 2014 We seek to gain novel insights into cancer mechanisms through a systematic analysis of complexes and their transcriptional regulation. Results: We integrated large-scale protein-interaction (PPI) and gene-expression datasets to identify complexes that exhibit significant changes in their expression across different conditions in cancer.
    [Show full text]
  • Rare Cnvs Provide Novel Insights Into the Molecular Basis of GH and IGF-1 Insensitivity
    6 183 E Cottrell and others CNVs in GH and IGF-1 183:6 581–595 Clinical Study insensitivity Rare CNVs provide novel insights into the molecular basis of GH and IGF-1 insensitivity Emily Cottrell1, Claudia P Cabrera2,3, Miho Ishida4, Sumana Chatterjee1, James Greening5, Neil Wright6, Artur Bossowski7, Leo Dunkel1, Asma Deeb8, Iman Al Basiri9, Stephen J Rose10, Avril Mason11, Susan Bint12, Joo Wook Ahn13, Vivian Hwa14, Louise A Metherell1, Gudrun E Moore4 and Helen L Storr1 1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, London, UK, 2Centre for Translational Bioinformatics, Queen Mary University of London, London, UK, 3NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK, 4University College London, Great Ormond Street Institute of Child Health, London, UK, 5University Hospitals of Leicester NHS Trust, Leicester, UK, 6The University of Sheffield Faculty of Medicine, Dentistry and Health, Sheffield, UK, 7Department of Pediatrics, Endocrinology and Diabetes with a Cardiology Unit, Medical University of Bialystok, Bialystok, Poland, 8Paediatric Endocrinology Department, Mafraq Hospital, Abu Dhabi, United Arab Emirates, 9Mubarak Al-kabeer Hospital, Jabriya, Kuwait, 10University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK, 11Royal Correspondence Hospital for Children, Glasgow, UK, 12Viapath, Guy’s Hospital, London, UK, 13Addenbrookes Hospital, Cambridge, UK, should be addressed and 14Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children’s Hospital Medical to H L Storr Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA Email [email protected] Abstract Objective: Copy number variation (CNV) has been associated with idiopathic short stature, small for gestational age and Silver-Russell syndrome (SRS).
    [Show full text]
  • Microrna-1258 Inhibits the Proliferation and Migration of Human Colorectal Cancer Cells Through Suppressing CKS1B Expression
    G C A T T A C G G C A T genes Article MicroRNA-1258 Inhibits the Proliferation and Migration of Human Colorectal Cancer Cells through Suppressing CKS1B Expression Jin-Seong Hwang 1,2, Eun-Jeong Jeong 1,3, Jinhyeon Choi 1, Yeo-Jin Lee 1,2, Eunsun Jung 1, Seon-Kyu Kim 4, Jeong-Ki Min 1,2, Tae-Su Han 1,* and Jang-Seong Kim 1,2,* 1 Biotherapeutics Translational Research Center, Division of Biomedical Science, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea; [email protected] (J.-S.H.); [email protected] (E.-J.J.); [email protected] (J.C.); [email protected] (Y.-J.L.); [email protected] (E.J.); [email protected] (J.-K.M.) 2 Department of Functional Genomics, University of Science and Technology, Daejeon 34141, Korea 3 Department of Biological Science, College of Natural Sciences, Wonkwang University, Iksan 570-450, Korea 4 Personalized Genomic Medicine Research Center, Division of Biomedical Science, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea; [email protected] * Correspondence: [email protected] (T.-S.H.); [email protected] (J.-S.K.) Received: 16 October 2019; Accepted: 7 November 2019; Published: 8 November 2019 Abstract: Increasing evidence has demonstrated that increased expression of cyclin-dependent kinase regulatory subunit 1B (CKS1B) is associated with the pathogenesis of many human cancers, including colorectal cancer (CRC). However, the regulatory mechanisms underlying the expression of CKS1B in CRC are not completely understood. Here, we investigate the role played by microRNAs in the expression of CKS1B and carcinogenesis in CRC.
    [Show full text]