非编码小RNA-34a(microRNA-34a)小分子调控剂的抗肝癌效应及作用机制研究

项目名称： 非编码小RNA-34a(microRNA-34a)小分子调控剂的抗肝癌效应及作用机制研究

项目编号： No.81472340

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 陈扬超

作者单位： 香港中文大学深圳研究院

项目金额： 75万元

中文摘要： 非编码小RNA-34a（miR-34a）是一个肿瘤抑癌基因，在包括肝癌在内的多种肿瘤中表达下调或沉默。人为表达miR-34a能显著抑制癌细胞生长，提示miR-34a是一个很有前景的癌症治疗靶标。在前期研究中, 我们成功构建了一个能用于小分子化合物文库筛选的miR-34a荧光报告系统，并筛选出一个能特异激活miR-34a 表达的小分子化合物3。化合物3在体外能显著抑制多种肝癌细胞的生长而对正常的人肝细胞则无毒性。在异位接种的肝癌裸鼠模型中，化合物3能明显地抑制肝癌生长。更令人兴奋的是，化合物3在体内显示出比肝癌靶向药物Sorafenib更强的抗癌活性！本课题将研究化合物3能否预防或延迟乙肝病毒导致的肝癌发生；并在转基因鼠中验证化合物3抗原发肝癌效应；还将研究化合物3调控miR-34a表达的分子机制。本课题研究结果将为开发以非编码小RNA为靶标的新的抗癌药物提供理论和实验依据。

中文关键词： 肝癌；microRNA-34a；小分子化合物；抗癌药；分子机制

英文摘要： MicroRNAs function as oncogenes or tumor suppressors by regulating gene expression and represent promising therapeutic targets for cancer. Small molecules modulating microRNAs expression would thus constitute potential anticancer agents. MicroRNA-34a (miR-34a) functions as a tumor suppressor and is downregulated or silenced in various cancers including hepatocellular carcinoma (HCC). MiR-34a therefore represents a promising therapeutic target for cancer. In our previous studies, a miR-34a luciferase report system was established for library screening of miR-34a modulators. One small molecule named compound 3 was identified as a specific miR-34a modulator. Compound 3 specifically activated miR-34a expression in HCC cells and down-regulated the expression of miR-34a targets. In vitro and in vivo studies demonstrated that compound 3 exhibited stronger anti-HCC activities than Sorafenib which is commonly used for HCC therapy in clinic. Further study would examine whether compound 3 could prevent and/or delay HCC development induced by hepatitis B virus X protein (HBX). The anti-HCC activities of compound 3 will be further examined in HBX transgenic mice model. Finally, we will delineate the mechanism underlying compound 3 modulation on miR-34a expression. Knowledge gained from this project would potentially lead to novel anti-HCC agent.

英文关键词： hepatocellular carcinoma;microRNA-34a;small molecule;anticancer agent;mechanism