长链非编码RNA FENDRR拷贝数变异调控Snail1基因影响人群肺癌发病和预后的研究

项目名称： 长链非编码RNA FENDRR拷贝数变异调控Snail1基因影响人群肺癌发病和预后的研究

项目编号： No.81473040

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： 吕嘉春

作者单位： 广州医科大学

项目金额： 85万元

中文摘要： 拷贝数变异(CNV)是影响疾病易感性的重要生物标志物。预实验检测了全基因组染色体变异位点，发现肺癌病例在16q24.1区域存在拷贝数变异热点；精细定位发现CNV-30795可能与肺癌发病存在关联，它位于长链非编码RNA(LncRNA) FENDRR第四外显子，可降低该LncRNA的表达，并与EMT调控因子Snail1基因高表达有关。生物信息分析发现Snail1基因启动子存在该LncRNA的结合序列，故推测FENDRR的拷贝数变异可降低其LncRNA表达并通过调控Snail1基因而影响肺癌的发生发展。本项目拟在两中心、大样本人群检测上述拷贝数变异和LncRNA表达，探讨其与肺癌发病和预后的关联；应用TALEN技术构建系列含拷贝数变异的肺癌模式细胞系，系统地运用多种功能实验方法探讨该CNV调控LncRNA及Snail1的机制，揭示FENDRR拷贝数变异的生物学功能，为肺癌防治提供科学依据。

中文关键词： 分子流行病学；拷贝数变异；长链非编码RNA；肺癌

英文摘要： Copy number variation (CNV) is an important biomarker for disease susceptibility. By using the array-based comparative genomic hybridization (aCGH) platform, we have previously identified a hotspot of CNVs at the chromosome 16q24.1 in lung cancer cases. Fine mapping of this region further revealed the CNV-30795 to be associated with lung cancer risk, which is located in the fourth exon of the long non-coding RNA (LncRNA) FENDRR. Preliminary experiments showed that the CNV can cause a down expression of FENDRR and is associated with up expression of the EMT regulator Snail1. Further bioinformatics analysis shown that there are binding site of FENDRR at the promoter region of Snail1. Thus, we hypothesized that the CNV of FENDRR is associated with lung cancer risk and prognosis via its effect on FENDRR as well as Snail1 expression. Here, this project intends to test the association between the CNV-30795 and lung cancer risk as well as prognosis by genotyping the CNV and detecting the LncRNA expression in a two-center and large population; to investigate the molecular mechanism of the CNV-30795 on regulating the expression of FENDRR and Snai1 by constructing a serious of human bronchial epithetical model cell lines carrying different copy number of the CNV-30795 via TALEN technique. Finally, a series functional assays will be used to illustrate the biological mechanism of CNV-30795 on modulating LncRNA FENDRR and Snail1 gene in lung cancer development. This project will help to clarify the mechanism of lung cancer pathology, and provide scientific evidences for prevention and treatment of lung cancer.

英文关键词： Molecular epidemiology;Copy number variation;Long non-coding RNA;Lung cancer