MicroRNAs as Targets for the Treatment of Hepatocellular Carcinoma

MicroRNAs作为肝癌治疗靶点的研究进展 我们研究了微小RNA表达改变在肝细胞癌（HCC）中的作用。 肝硬化与正常肝脏之间的关系，以及独特microRNA表达的改变是否 与转移性HCC相关，并与预后和复发相关。我们已经发现 对肝细胞癌和转移性疾病具有特异性的microRNA表达特征。 在这个项目中，我们建议评估几种microRNA的改变在发病机制中的作用。 以确定作为治疗干预的合适靶点的microRNA。我们将专注于 在HCC中过表达的miR 181 a/B、miR 21、miR 25、miR 221/222和miR 155以及miR 145， 在HCC中下调的miR 215、miR 125、miR 126、miR 192、miR 223和miR 122 a。我们也 发现了可能靶向维持（DNMT 1）和从头开始的3' UTR的microRNA。 （DNMT 3A，3B）DNA甲基转移酶。我们将评估这些microRNA的丢失是否会导致 DNMT的过度表达和与肝细胞相关的肿瘤抑制基因的沉默 致癌作用同时，我们将对DNA甲基转移酶DNMT 1的3'UTR进行测序， DNMT 3A和3B，以确定微小RNA的靶序列中的突变是否导致它们的突变。 上调。因此，拟议的研究旨在确定microRNA表达改变的作用， 在肝细胞癌的发生和发展中的作用，并验证microRNA作为靶点， 肝细胞癌的治疗干预。

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.