MicroRNAs as Targets for the Treatment of Hepatocellular Carcinoma

MicroRNA作为肝细胞癌治疗的靶点

• 批准号: 8197243
• 负责人: CARLO M CROCE
• 金额: $ 51.61万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197243
• 关键词: 3' Untranslated Regions; Algorithms; China; Chinese People; Cirrhosis; DNA Methyltransferase; DNA Methyltransferase 3B; DNA Modification Methylases; Development; Diagnosis; Disease; Down-Regulation; Excision; Female; Goals; Hepatocarcinogenesis; Knowledge; Liver; Liver Cirrhosis; Maintenance; Malignant Neoplasms; MicroRNAs; Molecular Profiling; Mutation; Neoplasm Metastasis; Outcome; Pathogenesis; Patients; Play; Primary carcinoma of the liver cells; Public Health; Recurrence; Role; Sampling; Solid; Specimen; Staging; Therapeutic Intervention; Time; Tissues; Tumor Suppressor Genes; Tumor Suppressor Proteins; Untranslated Regions; Up-Regulation; Validation; Venous; base; carcinogenesis; cohort; male; novel therapeutics; outcome forecast; overexpression; prognostic; tumor

MicroRNAs as Targets for the Treatment of Hepatocellular Carcinoma We have investigated the role of alterations in microRNA expression in hepatocellular carcinoma (HCC) and cirrhosis versus normal liver and whether alterations in the expression of unique microRNAs are associated with metastatic HCC and correlates with prognosis and recurrence. We have discovered microRNA expression signatures specific for hepatocellular carcinomas and for metastatic disease. In this project we propose to assess the role of alterations in several microRNAs in the pathogenesis of HCC to define microRNAs that are suitable targets for therapeutic intervention. We will focus on miR181a/b, miR21, miR25, miR221/222 and miR155 that are overexpressed in HCC and miR145, miR215, miR125, miR126, miR192, miR223, and miR122a, that are down-regulated in HCC. We also found microRNAs that potentially target the 3' UTR of the maintenance (DNMT1) and the de novo (DNMT3A, 3B) DNA methyltransferases. We will assess whether loss of these microRNAs result in overexpression of DNMTs and silencing of tumor suppressor genes associated to hepatocellular carcinogenesis. At the same time we will sequence the 3' UTRs of the DNA methyltransferases DNMT1, DNMT3A and 3B to determine whether mutations in target sequences of microRNAs result in their upregulation. Thus the proposed study intends to establish the role of alterations in microRNA expression in the initiation and progression of hepatocellular carcinoma and to validate microRNAs as targets for therapeutic intervention in hepatocellular carcinoma.

作为肝细胞癌治疗靶点的microRNAs 我们研究了microRNA表达的改变在肝细胞癌中的作用。 以及独特的microRNAs的表达是否发生了变化 与转移性肝癌相关，并与预后和复发相关。我们发现 肝细胞癌和转移性疾病特有的microRNA表达特征。 在这个项目中，我们建议评估几个microRNAs的改变在发病机制中的作用。 以确定适合作为治疗干预靶点的microRNAs。我们将重点关注 在肝癌和miR145中高表达的miR181a/b、miR21、miR25、miR221/222和miR155， MiR215、miR125、miR126、miR192、miR223和miR122a在肝细胞癌中表达下调。我们也 发现潜在靶向维持(DNMT1)和从头开始的3‘UTR的microRNAs (DNMT3A，3B)DNA甲基转移酶。我们将评估这些microRNA的丢失是否会导致 肝细胞癌相关基因DNMT的过表达和抑癌基因的沉默 致癌。同时，我们将对DNA甲基转移酶DNMT1的3‘UTRs进行测序， DNMT3A和3B，以确定microRNAs目标序列的突变是否导致其 上调。因此，这项拟议的研究旨在确定microRNA表达的变化的作用 在肝细胞癌的发生和发展中的作用，并验证作为靶点的microRNAs 肝细胞癌的治疗干预。