DNA修复基因3'-UTR遗传变异与肝细胞肝癌发生风险及其机制研究

Guangxi is one of areas for the highest incidence of Hepacellular carcinoma (HCC) in China. HCC is also the leading cause of cancer death in Guangxi. Both environmental and genetic factors contribute to the etiology of HCC, but the mechanisms of HCC are not clear. Cellular DNA repair system plays a critical role in cell malignant transformation. miRNAs negatively regulate gene expression by recognizing partially complementary sequences in the 3'-UTR of their target mRNAs. It has been known that miRNAs play a major role in cancer development. SNPs in the miRNA-binding sites (mir-SNPs) within the 3'-UTR may interfere with miRNA gene regulation and affect cancer susceptibility by altering miRNA-mRNA interactions. mir-SNPs within the 3'-UTR of the important DNA repair genes were predicted and screened by using bioinformatics approaches in our preliminary work. In this molecular case-control study, we will investigate the associations of the screened mir-SNPs and interactions of gene-gene/gene-environment (HBV infection, smoking and drinking, etc.) with HCC risk and indentify significant mir-SNPs associated with HCC risk. Furthermore, the biological function of significant mir-SNPs will be investigated using a series of cell-based assays and molecular biology techniques. This study may elucidate the biological mechanism of genetic variants in the 3'-UTR of DNA repair genes in the pathogenesis of HCC, and provide important evidence for personal prevention, intervention and treatment of HCC in future.

广西是我国肝细胞肝癌(HCC)高发区，其死亡率居广西肿瘤死因谱首位。HCC发生是环境与遗传因素共同作用的结果，但其发病机制尚不很清楚。人类细胞DNA修复系统在防止细胞恶性转化过程起关键作用。miRNA通过与其靶mRNA 3'-UTR结合，导致mRNA降解或翻译抑制，从而负调控基因表达，与肿瘤发生密切相关。3'-UTR miRNA结合区域SNP可通过影响miRNA与其靶序列结合而影响miRNA功能。本课题基于生物信息方法筛选出的DNA修复基因3'-UTR miRNA结合区域SNPs，运用病例对照研究方法，探讨SNPs与HCC发生风险的关系，分析基因-基因及基因-环境交互作用；在此基础上，采用系列细胞、分子生物学方法，探讨显著关联SNPs的功能学意义，揭示DNA修复基因3'-UTR遗传变异在HCC发病中的可能生物学机制，筛选出HCC易感性标志物，为HCC个体化预防、干预和治疗等提供重要理论依据

广西是我国肝细胞肝癌(HCC)高发区，其死亡率居广西肿瘤死因谱首位。HCC 发生是环境与遗传因素共同作用的结果，但其发病机制尚不很清楚。人类细胞 DNA 修复系统在防止细胞恶性转化过程起关键作用。miRNA 通过与其靶 mRNA 3'-UTR 结合，导致 mRNA 降解或翻译抑制，从而负调控基因表达，与肿瘤发生密切相关。3'-UTR miRNA 结合区域 SNP 可通过影响 miRNA 与其靶序列结合而影响 miRNA 功能。本课题选择了位于19个DNA修复基因3’-UTR区域miRNAs结合位点的23个SNPs，采用以医院为基础的病例-对照研究方法，研究这些SNPs及其与吸烟、饮酒、HBV感染等环境暴露因素的交互作用与HCC易感性的关系。我们通过对选取的1114例确诊的HCC新发病例和1208例非肿瘤患者进行候选SNPs基因分型，应用单因素、多因素Logistic回归统计方法，评价其基因型频率分布及其与HCC遗传易感性的关系。结果发现，DDB2基因rs1050244位点与HBV感染在HCC发病风险中存在交互作用，其T等位基因是广西地区HBV感染阴性人群HCC的保护等位基因；LIG4 基因rs10131位点分别与吸烟、饮酒在HCC发病风险中存在交互作用，其C等位基因是广西地区吸烟、饮酒人群HCC的危险等位基因；RAD51D基因rs12947947、rs28363292位点在HCC发病风险中存在联合作用，rs28363292位点G等位基因可能是广西地区人群HCC的危险等位基因；RAD52基因rsl051669、rsl051672位点分别与性别在HCC发病风险中存在交互作用， rsl051669位点C等位基因和rsl051672 位点G等位基因可能是广西地区女性人群HCC的危险等位基因。该研究结果提示DNA修复基因3’-UTR区域miRNAs结合位点上的SNPs联合作用或与吸烟、饮酒、HBV感染等环境暴露因素的交互作用对HCC的遗传易感性有影响。