食管癌易感基因CAPS8和RIP3的遗传变异及其功能研究

Esophageal cancer is one of the most malignant cancers in China. Esophageal cancer candidate gene and genome-wide association study (GWAS) found that over 10 susceptibility gene located in 9 chromosome segments with different loci and their susceptible sites were confirmed by the crowd large sample validation. However, the identification of these common genetic variants of pathogenic molecular mechanism is unclear. Based on the works, this study we proposed to investigate the molecular mechanism of CASP8 and its isomers and RIP3 expression in tumorigenesis of esophageal cancer through different approaches, e.g. a multi-stage expression quantitative trait loci (eQTL) analysis, proteome-wide analysis of disease associated SNPs (PWAS) and epigenome-wide association study (EWAS). For both apoptosis and necrosis in regulating gene - CASP8 and its isomers and RIP3, we try to identify specific environmental factors related to epigenetics, such as smoking or alcohol drinking by EWAS; and to isolate the specific binding of transcription factors which bound on the susceptibility loci by PWAS respectively. After serious studies of gene function we hope to better understand the interaction of the acquired specific environmental factors and susceptibility genes, understanding the molecular mechanism of esophageal esophageal cancer susceptibility gene and its associated sites.

食管癌候选基因和全基因组关联研究（GWAS）发现并经人群大样本验证了位于9个染色体区段的10多个易感基因及其易感位点。然而，所鉴定的这些常见基因变异的致病分子机理尚不清楚。本研究拟在食管癌候选基因关联研究和GWAS研究的工作基础上，针对两个细胞凋亡与坏死调控基因--CASP8及其异构体和RIP3，采用多阶段表达数量性状位点（eQTL）分析、全蛋白质组水平疾病相关SNP分析（PWAS）、特定环境因素相关的全基因组表观遗传学分析（EWAS）和基因功能研究相结合的方法，分离鉴定易感基因位点特异结合的转录因子及其调控基因、认识后天特定环境因素与易感基因的交互作用，认识食管癌易感基因及其相关位点在食管癌变中的分子机理。

食管癌候选基因关联研究显示，多个参与细胞凋亡、细胞周期调控、DNA损伤修复和致癌物代谢等基因的异常表达可能在食管癌癌变过程中发挥重要作用。围绕细胞凋亡和坏死相关基因CASP8和RIP3，以及ABCC4、GPC1和NDRG1等其他消化肿瘤易感基因在调控食管癌细胞凋亡和坏死及细胞癌变中的分子机理，本项目开展了系列研究工作。发现调控CASP8的第二启动子、易感基因RIP3具有调控食管癌化疗敏感性的新功能、发现食管癌易感基因ABCC4、NDRG1及其促进细胞癌变的机理；探讨了小分子化合物YM155和EDHB诱导食管癌细胞死亡和干预食管粘膜早期病变的分子机理，以及用基于磁珠的MALDI-TOF-MS蛋白质组分析鉴定了食管癌血清多肽标志物等。发表标注项目编号的SCI论文19篇（IF大于5文章8篇）、核心期刊文章6篇和综述3篇；授权国家发明专利3项；获北京市科技进步三等奖1项（排名1），培养研究生14人，博士后1人，1人晋升高级职称。

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