Aberrant DNA Methylation of MicroRNA Genes in Hepatocellular Carcinoma (HCC)

肝细胞癌 (HCC) 中 MicroRNA 基因的异常 DNA 甲基化

• 批准号: 8330235
• 负责人: Jing Shen
• 金额: $ 8万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-08 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8330235
• 关键词: Aberrant DNA Methylation; Academic Medical Centers; Aflatoxin B1; Alcohol abuse; Animal Model; Apoptosis; Biological; Cancer cell line; Cell Proliferation; Cirrhosis; CpG Islands; DNA Methylation; Data; Death Rate; Development; Down-Regulation; Early Diagnosis; Environmental Carcinogens; Epidemiologic Studies; Epigenetic Process; Event; Formalin; Freezing; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Genetic; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Hepatocarcinogenesis; Histologic; Human; Incidence; Lead; Liver; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Measures; Mediating; Methylation; MicroRNAs; Nature; Oncogene Activation; Paraffin Embedding; Pathway interactions; Patients; Pattern; Physiological Processes; Pilot Projects; Play; Primary carcinoma of the liver cells; Principal Investigator; Process; Promoter Regions; Regulator Genes; Risk Assessment; Role; Sample Size; Specimen; Subgroup; Testing; Tissue Banking; Tissue Banks; Tissues; Toxin; Transcription Initiation Site; Treatment Efficacy; Tumor Suppressor Genes; Tumor Tissue; United States; Viral; Virus; alcohol exposure; clinical application; improved; men; prognostic; programs; promoter; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Tumor suppressor gene silencing by promoter DNA methylation is an important mechanism of tumorigenesis, including in hepatocellular carcinoma (HCC). MicroRNAs (miRNAs), as key regulators of gene expression, play a critical role in cell proliferation, differentiation and apoptosis. Tumor suppressive miRNAs harboring CpG-islands in their promoter regions may also be sensitive to methylation-mediated silencing. Previous studies found that the deregulated expression of tumor suppressive miRNAs (miR-1-1, miR-124, and miR-203) might be due to aberrant DNA methylation. These limited data were obtained from different animal models, cancer cell lines or from a study of a small number of frozen tumor tissues. The methylation status of many miRNAs with tumor suppressive functions is largely unknown, especially for those specifically expressed in liver tissues (miR-122, miR-152, miR-194, miR-199 and miR-215). Our hypothesis is that DNA methylation in tumor suppressive miRNA genes is a common event influencing relevant mature miRNA expression, and contributes to differentiate HCC tumor and non-tumor tissues. The two specific aims are: (1) To examine whether a panel of tumor suppressive miRNA genes have significantly higher levels of DNA methylation in HCC tumor tissues compared with adjacent non-tumor tissues, and test whether the miRNA methylation levels are different for hepatitis B virus (HBV) and hepatitis C virus (HCV)-related HCC; (2) To examine whether a subgroup of miRNA genes showing significant methylation alterations are associated with the down-regulation of relevant mature miRNA expression. A case-only study will be conducted using a well-established, formalin- fixed, paraffin-embedded (FFPE) tissue bank of US HCC patients at Columbia University Medical Center. Totally, 120 histologically confirmed HCC cases with tumor and adjacent non-tumor tissues and HBV/HCV infection data are available for the current study. This pilot study will provide valuable preliminary data to understand the role of miRNA gene methylation in distinguishing HCC malignant tissue from non-tumor tissues. These methylation markers have potential clinical applications to improve risk assessment, early diagnosis and prognostic prediction, and may even possibly improve treatment because of the reversible nature of epigenetic changes. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

描述（由申请人提供）：启动子DNA甲基化肿瘤抑制基因沉默是肿瘤发生的重要机制，包括在肝细胞癌（HCC）中。 MicroRNA（miRNA）作为基因表达的关键调节剂，在细胞增殖，分化和凋亡中起关键作用。在其启动子区域内有CpG岛的肿瘤抑制miRNA也可能对甲基化介导的沉默敏感。先前的研究发现，肿瘤抑制miRNA（miR-1-1，miR-124和miR-203）的表达可能是由于异常的DNA甲基化引起的。这些有限的数据是从不同动物模型，癌细胞系或少量冷冻肿瘤组织的研究中获得的。许多具有肿瘤抑制功能的miRNA的甲基化状态在很大程度上是未知的，尤其是对于在肝组织中特异性表达的甲基化状态（miR-122，miR-152，miR-152，miR-194，miR-199，miR-199和miR-215）。我们的假设是，肿瘤抑制miRNA基因中的DNA甲基化是影响相关成熟miRNA表达的常见事件，并有助于区分HCC肿瘤和非肿瘤组织。这两个具体目的是：（1）检查与邻近的非肿瘤组织相比，HCC肿瘤组织中抑制肿瘤抑制miRNA基因的DNA甲基化水平明显更高，并且测试miRNA甲基化水平是否不同于乙型肝炎的水平。病毒（HBV）和丙型肝炎病毒（HCV）相关的HCC； （2）检查显示出显着甲基化改变的miRNA基因的亚组是否与相关成熟miRNA表达的下调有关。将使用哥伦比亚大学医学中心的美国HCC患者的良好，福音，石蜡包裹的（FFPE）组织库进行一项仅病例研究。总的来说，有120例具有肿瘤和邻近非肿瘤组织和HBV/HCV感染数据的组织学确认的HCC病例可用于当前研究。这项初步研究将提供有价值的初步数据，以了解miRNA基因甲基化在区分HCC恶性组织和非肿瘤组织中的作用。这些甲基化标记具有潜在的临床应用，以改善风险评估，早期诊断和预后预测，甚至可能由于表观遗传变化的可逆性而改善治疗。 PHS 398/2590（修订版06/09）页面延续格式页面