PI3K/Akt/mTOR信号通路基因遗传变异与胃癌易感及其机制研究

PI3K/Akt/mTOR pathway is involving in the occurrence and development of cancers, which has been considered as a novel target in clinical therapy. Until now, accumulated studies have identified that aberrant expression and phosphorylation of PI3K/Akt/mTOR pathway were associated with risk of gastric cancer. Our previous results showed that rs2295080 polymorphisms of mTOR in the PI3K/Akt/mTOR pathway was associated with the risk of gastric cancer by regulating mTOR gene expression activity. In this study, we will use the bioinformatics to evaluate the associations between the function of SNPs in PI3K/Akt/mTOR pathway and the risk of gastric cancer in the Chinese population in two-stage case-control studies. Furthermore, the molecular biological methods including bioinformatics, molecular clones, reporter genes, site mutation and other methods, will be performed to confirm functional roles of these SNPs. Based on these results, we will systematically analyse these influences of the SNPs in gene expression and phosphorylation by eQTL methods. As a result, our data could reveal the mechanism of SNPs in gastric cancer and provide the important instruction for screening of susceptible individuals, personal prevention and intervention.

PI3K/Akt/mTOR信号通路广泛参与肿瘤的发生发展，并成为肿瘤治疗的新靶点。研究表明，PI3K/Akt/mTOR信号通路的异常表达及磷酸化程度与胃癌的发生发展密切相关。我们前期研究证实,PI3K/Akt/mTOR信号通路上的mTOR基因多态性位点rs2295080可通过调控mTOR 基因表达的活性，影响胃癌发生的危险性。本课题拟通过生物信息学方法，运用两阶段分子流行病学病例-对照研究方法，探讨PI3K/Akt/mTOR信号通路关键基因上单核苷酸多态性（SNPs）与中国汉族人群胃癌易感的关联性。同时结合基因本体论等方法，应用生物信息学、分子克隆、报告基因、定点突变等技术,探讨各SNPs位点对所在基因表达的影响类型及其分子机制。在此基础上，采用eQTL方法系统的分析各SNPs位点的效应强度，为深入揭示胃癌发病机制提供理论依据，并为今后易感人群的筛查以及胃癌的个体化预防和干预提供重要参考。

PI3K/Akt/mTOR信号通路广泛参与肿瘤的发生发展，在肿瘤预防及治疗中具有重要的临床研究价值。已有研究表明，PI3K/Akt/mTOR信号通路的异常表达及磷酸化程度与胃癌的发生发展密切相关。本课题拟探讨PI3K/Akt/mTOR信号通路关键基因上单核苷酸多态性（SNPs）与中国汉族人群胃癌易感的关联性及其可能的生物学机制。在大样本的病例-对照研究中，仅发现PIK3R3 rs7536272和mTOR rs2295080两个多态性位点与胃癌的发生显著相关。本研究发现，与携带PIK3R3 rs7536272AA基因型的个体相比，AG基因型个体罹患胃癌的风险显著增加（调整OR = 1.34, 95% CI = 1.09-1.65）。双荧光素酶报告基因实验和eQTL分析结果表明G等位基因能够显著增加PIK3R3转录活性，提高其mRNA的表达水平。与mTOR rs2295080T等位基因相比，G等位基因对胃癌发病风险呈明显的保护作用（调整OR = 0.77, 95% CI = 0.65-0.92）。功能学实验发现，rs2295080G等位基因能够抑制mTOR基因转录活性、降低其与转录因子的结合能力，从而降低mTOR的表达水平，对胃癌的发生起到保护性作用。本研究揭示了PI3K/Akt/mTOR信号通路中与胃癌易感性相关的SNPs，并采用离体和在体相结合的技术手段，探讨了候选SNPs对基因转录活性、转录因子结合以及mRNA表达水平的影响，进一步揭示PI3K/Akt/mTOR信号通路基因参与胃癌发生发展的生物学机制，并为今后胃癌的预防和治疗提供重要理论依据。