靶向增强子的小激活RNA激活前列腺癌细胞E-钙粘蛋白表达的机制初探

项目名称： 靶向增强子的小激活RNA激活前列腺癌细胞E-钙粘蛋白表达的机制初探

项目编号： No.81502215

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 茅叶青

作者单位： 浙江大学

项目金额： 18万元

中文摘要： 自从2006年，RNA激活（RNAa）和小激活双链RNA分子（saRNA）的概念首次被提出以来，已经有越来越多的基因被证实可以借助RNAa被激活表达，RNAa是真核细胞的一种内源性的基因调控手段。传统的RNAa技术仅针对基因的启动子区我们在前期研究中发现RNAa对易感基因的激活能力有限，鉴于越来越多的证据显示，增强子拥有和启动子相似的表遗传学特征，并在调控基因表达和肿瘤发生中同样具有重要的意义，我们开始尝试设计靶向增强子序列的saRNA。在本研究中，我们以钙黏蛋白E（CDH1）为对象，设计并筛选能靶向激活CDH1增强子的saRNA（esaRNA），并初获成功；接下来我们将进一步全面地评价其功能，用体内试验评估其治疗意义和临床应用前景；为初步探索其作用机制，我们将主要从组蛋白修饰等角度去考察esaRNA 对细胞表遗传学机制的影响；最后，我们希望在此基础上进一步拓展，通过筛查能靶向激活CDH1

中文关键词： 前列腺肿瘤；增强子；启动子；RNAa；小激活RNA

英文摘要： Our reseach team has engaged in saRNA (small activation RNA) study for years since 2006 when RNA activation was first discovered and have progressively identified a series of promoter-targeted saRNAs for tumor suppressor genes. However, a drawback still lies in the limited activation effect on targeted gene by the saRNA, which was proven to be hard to overcome. Recently, more and more evidence has confirmed the important role of enhancer in cancerous gene regulation; enhancers are proved to share similar epigenetic features as promoters. Therefore, we were enlightened to modify the RNAa tech by enhancer-targeted way. In the preliminary study, the enhancer-targeted small RNA(esaRNA) for E-cadherin (CDH1) was identified and confirmed; more comprehensive assessment of its function, as well as further investigation of its epigenetic alteration by means of advanced sequencing tech and bioinformatic tech is absolutely necessary. These results not only provide evidence that upregulation of therapeutic gene by saRNAs may be a potential therapeutic strategy to treat prosate cancer, but also an annotation of universality of RNAa in gene regualtion.

英文关键词： prostate caner;enhancer;promoter;RNAa;small activation RNA