摘要
目的:探索染色体1q22区域易感基因在胃癌发生中的作用和机制。方法:基于genotype-tissue expression(GTEx)数据库,鉴定候选易感基因;通过人群样本进行基因差异表达分析,并通过细胞和动物实验探究易感基因在胃癌发生中的作用;通过全转录组测序探究候选易感基因在胃癌发生中参与的下游通路和机制。结果:表达数量性状基因座(expression quantitative trait loci,eQTL)分析证实rs760077基因型与THBS3、GBA和GBAP1基因的表达水平均显著相关(P值分别为1.20×10^-21,1.80×10^-4和3.49×10^-17)。差异表达分析和功能学实验证实GBAP1在胃癌组织中呈现高表达状态,并且敲低GBAP1后能够显著抑制胃癌细胞增殖能力。全转录组测序表明GBAP1能够影响PHGDH、PSAT1和PSPH基因的表达水平并参与包括甘氨酸、丝氨酸、苏氨酸代谢和一碳代谢在内的多种代谢通路。结论:本研究证实1q22区域的遗传变异可以通过调控促癌基因GBAP1的表达,影响氨基酸合成代谢通路关键酶基因PHGDH、PSAT1和PSPH的表达,从而促进胃癌的发生。
Objective:To elucidate the mechanisms of susceptibility genes on chromosome 1q22 for gastric cancer(GC)development.Methods:Using the genotype-tissue expression database,the associations between independent effect loci and the expression levels of genes around the loci were analyzed.For the candidate susceptibility genes,differential gene expression(DGE)analysis was performed using population samples.The role of the susceptibility genes in the development of GC was explored through in vitro and in vivo experiments.The downstream pathways and mechanisms involved in the pathogenesis of GC were further explored through RNA sequencing.Results:Expression quantitative trait loci(eQTL)analysis confirmed that the rs760077 genotype was significantly correlated with the expression levels of THBS3,GBA,and GBAP1(P-values were 1.20×10^-21,1.80×10^-4,and 3.49×10^-17,respectively).DGE analysis and cell phenotype experiments confirmed that GBAP1 was highly expressed in GC tissues.The knockdown of GBAP1 significantly inhibited the proliferation of GC cells and reduced the growth of xenograft tumors in nude mice.RNA sequencing showed that GBAP1 could affect the expression levels of PHGDH,PSAT1,and PSPH and participate in various metabolic pathways,including those involved in glycine,serine,threonine,and carbon metabolism.Conclusions:This study confirmed that genetic variation in the 1q22 region could affect the expression of PHGDH,PSAT1,and PSPH,which code for key enzymes in amino acid synthesis,by regulating the expression of the pro-oncogene GBAP1,thereby promoting the occurrence of GC.
作者
颜财旺
高志颖
黄童童
靳光付
Caiwang Yan;Zhiying Gao;Tongtong Huang;Guangfu Jin(Department of Epidemiology,Center for Global Health,School of Public Health,Nanjing Medical University,Nanjing 211166,China;Department of Gastroenterology,The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University,Huai'an 223300,China)
出处
《中国肿瘤临床》
CAS
CSCD
北大核心
2020年第21期1108-1114,共7页
Chinese Journal of Clinical Oncology
基金
国家重点研发计划“重大慢性非传染性疾病防控研究”重点专项课题(编号:2016YFC1302703)
国家自然科学基金面上项目(编号:81872702)
中国博士后科学基金委员会项目(编号:2019TQ0157,2020M671546)资助。
