影响转录因子c-Myc结合的功能性遗传变异系统发掘及其与肝癌易感性的关系研究

项目名称： 影响转录因子c-Myc结合的功能性遗传变异系统发掘及其与肝癌易感性的关系研究

项目编号： No.81201586

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 杨明

作者单位： 北京化工大学

项目金额： 23万元

中文摘要： 原癌基因c-Myc可通过特异结合靶基因E-box核心元件(5'-CACGTG-3')调控众多下游基因，从而参与肝癌的发生发展过程。我们的前期研究显示，在肝癌基因组12256个c-Myc结合位点中，存在34436个单核苷酸多态。生物信息学筛查表明，上述多态中，位于E-box元件、并可能导致c-Myc与DNA结合异常的共20个。对其中5个遗传多态基因分型后，我们发现，位于HNF1A基因潜在增强子中的rs1180015多态可影响增强子活性，并与肝癌易感性显著相关。本研究着眼于进一步揭示上述20个遗传多态中与肝癌易感性显著相关的位点，并通过EMSA和报告基因实验等一系列体内外实验，阐明这些遗传多态影响c-Myc对靶基因调控的分子机制。在"后GWAS时代"，本项目为深入研究功能性遗传变异与肝癌易感性的关系提供了一种新策略，并为进一步理解c-Myc转录调控个体差异的分子基础及肝癌发病机制提供了新思路。

中文关键词： 肝癌；单核苷酸多态性；全基因组范畴内的关联研究；抑癌基因；

英文摘要： Oncoprotein c-Myc can bind to the E-box DNA element (5'-CACGTG-3 ') and regulate many downstream target genes, which participate in the development and progression of hepatocellular carcinoma (HCC). Our previous studies showed that there are 34436 single nucleotide polymorphisms (SNP) located in the 12256 c-Myc binding sites in the HCC genome. Bioinformatics screening results revealed that there are 20 SNPs which locate in the E-box element and may interrupt binding of c-Myc to DNA. After genotyping 5 SNPs in 800 HCC cases and 800 age- and sex-matched healthy controls (the discovery cohort), we found that rs1180015 polymorphism, locating in a potential enhancer of the HNF1A gene, is significantly associated with increased HCC risk. Dual-luciferase reporter gene assays showed that rs1180015G→C change could lead to significantly reduced enhancer activities in both HepG2 and SMMC7721 cells. In this proposal, we are going to genotype the other 15 SNPs in the discovery cohort and validated the results in 1700 HCC cases and 1700 controls from two medical centers. The biological role of the HCC susceptibility-related SNPs will be examined by a set of biochemical assays, including EMSA and dual-luciferase reporter gene assays. After clarifying how the SNPs influence function of c-Myc in vitro, we will also detect expres

英文关键词： Hepatocellular carcinoma；single nucleotide polymorphism；GWAS；tumor suppressor；