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: 8190296
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190296
• 关键词: Aberrant DNA Methylation; Academic Medical Centers; Aflatoxin B1; Alcohol abuse; Animal Model; Apoptosis; Biological; Cancer cell line; Cell Proliferation; 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 PUBLIC HEALTH RELEVANCE: Aberrant DNA methylation is a frequent event occurring early in HCC tumorigenesis. This pilot study will provide initial evidence on the critical role of tumor suppressive miRNA genes' methylation and expression in identifying HCC malignant tissue. It will provide preliminary data to support expanded epidemiological studies that should lead to long term improvements in HCC risk assessment, early diagnosis and efficient treatment.

描述（由申请人提供）：启动子 DNA 甲基化导致的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因子，在细胞增殖、分化和凋亡中发挥着关键作用。在其启动子区域含有 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，肿瘤抑制性 miRNA（miR-1-1、miR-124 和 miR-203）的表达失调可能是由于异常的 DNA 甲基化造成的。这些有限的数据是从不同的动物模型、癌细胞系或对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 的甲基化状态很大程度上未知，特别是那些在肝组织中特异性表达的 miRNA（miR-122、miR-152、miR-194、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。两个具体目标是：（1）检查一组抑癌miRNA基因在HCC肿瘤组织中是否具有显着高于邻近非肿瘤组织的DNA甲基化水平，并测试乙型肝炎的miRNA甲基化水平是否不同病毒（HBV）和丙型肝炎病毒（HCV）相关的肝癌； (2) 检测显示显着甲基化改变的 miRNA 基因亚群是否与相关成熟 miRNA 表达下调相关。将使用哥伦比亚大学医学中心的美国 HCC 患者成熟的福尔马林固定石蜡包埋 (FFPE) 组织库进行仅病例研究。目前的研究总共有 120 例经组织学证实的具有肿瘤和邻近非肿瘤组织的 HCC 病例以及 HBV/HCV 感染数据。这项初步研究将为了解 miRNA 基因甲基化在区分 HCC 恶性组织与非肿瘤组织中的作用提供有价值的初步数据。这些甲基化标记物具有潜在的临床应用，可改善风险评估、早期诊断和预后预测，由于表观遗传变化的可逆性，甚至可能改善治疗。 PHS 398/2590（修订版 06/09） 页面延续 格式页面 公共卫生相关性：异常 DNA 甲基化是 HCC 肿瘤发生早期的常见事件。这项初步研究将为肿瘤抑制 miRNA 基因的甲基化和表达在识别 HCC 恶性组织中的关键作用提供初步证据。它将提供初步数据来支持扩大的流行病学研究，从而长期改善 HCC 风险评估、早期诊断和有效治疗。