PRKAA1基因遗传变异与胃癌的相关性及其功能机制研究

项目名称： PRKAA1基因遗传变异与胃癌的相关性及其功能机制研究

项目编号： No.81502435

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 张杨梅

作者单位： 徐州医科大学

项目金额： 18万元

中文摘要： 胃癌是最常见的恶性肿瘤之一。PRKAA1基因编码AMPK激酶的关键催化亚单位，而研究表明AMPK通过多种信号通路参与调控肿瘤的发生发展。全基因组关联分析将胃癌的一个易感基因定位于5p13.1（PRKAA1基因的所在区域）。通过进一步生物信息学分析，发现PRKAA1启动子区SNPrs461404、rs10035235分别位于转录因子NF-κB1、RFX3的结合区域，而第一内含子区SNP rs13361707正好处于转录因子GATA1的结合区域。荧光素酶报告基因实验也证实不同等位基因的序列所驱动的荧光素酶表达量存在着显著的差异，说明这些位点具备一定的功能。本课题拟在前期工作的基础上精确定位PRKAA1基因上的功能位点，分析其功能学机制，探讨其与肿瘤的易感发生、临床表型及预后之间的关系。本研究将建立功能性肿瘤相关基因多态性位点的分析流程，为今后胃癌的个体化治疗和预防提供重要理论依据。

中文关键词： 胃癌；腺苷单磷酸活化蛋白激酶a1；单核苷酸多态性；AMPK信号转导通路

英文摘要： Gastric cancer(GC) is one of the most common malignant tumors. The PRKAA1 protein, the product of PRKAA1 gene (protein kinase, AMP-activated, alpha 1 catalytic subunit), is one of the key subunits of the mammalian 5′-AMP–activated protein kinase (AMPK), which has been reported to be involved in the development of tumors through various signaling ways. Genome-wide association analysis located one of the susceptibility genes of GC in 5p13.1 (PRKAA1 gene region). By bioinformatics analysis,we found that rs461404 and rs10035235，which are both located in the promoter of PRKAA1 gene，lie respectively in combination region of transcription factor NF-κB1and RFX3. Meanwhile，SNP rs13361707 located in the first intron of the PRKAA1 lies just in the combination region of transcription factor GATA1 and PRKAA1. Lacoperator-containing luciferase reporter assay also demonstrated the significant differences of luciferase expression level driven by different sequences containing various alleles. Based on the fore-working, we can pinpoint the function domain of PRKAA1 gene, analyze its functional mechanism, and explore the relationship between the function domain and tumor susceptibility, clinical phenitype, survival time. The study will establish analysis process of functional tumor-associated SNPs and provide a kind of important theory basis for individualized therapy and efficacy prediction.

英文关键词： Gastric cancer;PRKAA1; SNPs;AMPK signaling pathway