ADCY9基因介导吉西他滨肺腺癌耐药的系统生物学研究  

Systemic biological study of ADCY9 gene mediating gemcitabine resistance in lung adenocarcinoma

作　　者：王桂平 梁杰聪 张彦焘 李智斌 WANG Guiping;LIANG Jiecong;ZHANG Yantao;LI Zhibing(Department of Pharmacy,Guangzhou Health Science College,Guangzhou 510180,China;Department of Surgery,Guangzhou Women and Children′s Medical Center,Guangzhou 510623,China)

机构地区：[1]广州卫生职业技术学院药学系,广东广州510180 [2]广州市妇女儿童医疗中心外科,广东广州510623

出　　处：《药学研究》2019年第12期729-734,共6页Journal of Pharmaceutical Research

基　　金：广东省省级科技计划项目(No.2016A020215213);广州市教育局市属高校科研项目(No.1201620370)

摘　　要：目的基于系统生物学模式筛选吉西他滨肺腺癌耐药的hub基因,探讨hub基因ADCY9介导吉西他滨肺腺癌耐药的分子机制。方法采用dChip进行吉西他滨耐药差异基因分析;通过DAVID进行基因注释、生物信号通路功能聚类分析;采用STRING构建蛋白质相互作用网络,并筛选hub基因;使用Oncomine和TCGA数据库分析候选hub基因在肺腺癌等肿瘤组织中的表达情况,并进行共表达基因分析。结果获得吉西他滨肺腺癌耐药差异基因391个,其中上调基因80个,下调基因311个;构建了蛋白质相互作用网络,获得BDKRB2、BDKRB1、POMC、ADCY9等10个hub基因;Oncomine和TCGA数据库分析显示,ADCY9基因在肺腺癌中明显表达下调,生存分析发现ADCY9基因高水平表达可降低肺腺癌总体死亡风险(log rank P=0.014);吉西他滨肺腺癌耐药组中,ADCY9基因出现下调表达,ADCY9基因与耐药相关基因SMAD6存在相似的表达,相关性显著(P=5.6×10^-27,R=0.44)。ADCY9共表达基因涉及多条肿瘤耐药途径如Rho蛋白及G蛋白信号转导、MAPKK活化、钙离子负性转运等。结论ADCY9基因可能是一种重要的肺腺癌预后标志,也可能在吉西他滨肺腺癌耐药的发生机制中起重要作用。Objective To screen the hub gene of gemcitabine resistance in lung adenocarcinoma based on the model of system biology,and to explore the molecular mechanism of a hub gene ADCY9 mediating gemcitabine resistance in lung adenocarcinoma.Methods dChip soft was used to analyze difference expression genes(DEGs)of gemcitabine resistance.Gene annotation and signal pathway clustering analysis were performed by DAVID.Protein-protein interaction(PPI)network was constructed with STRING and hub genes were screened by cytoscape.Oncomine and TCGA databases were used to analyze the expression of candidate hub genes in lung adenocarcinoma and other tumor tissues,and the co-expression genes of ADCY9 were analyzed using Oncomine.Results 391 DEGs for gemcitabine resistance were obtained,including 80 up-regulated genes and 311 down-regulated genes.10 hub genes(BDKRB2,BDKRB1,POMC and ADCY9,etc)were obtained based on PPI network.Results from Oncomine and TCGA database analysis showed that ADCY9 gene expression was significantly down-regulated in lung adenocarcinoma,and high level of ADCY9 gene expression was found to reduce the overall risk of lung adenocarcinoma death(log rank P=0.014).mRNA expression of ADCY9 was down-regulated in gemcitabine-resistant lung adenocarcinoma,of in was found,and a drug-resistant related gene SMAD6 was a highly relevant co-expression gene of ADCY9,with a significant correlation(P=5.6×10^-27,R=0.44).Co-expression genes of ADCY9 involves multiple tumor resistance pathways,such as Rho protein and G protein signal transduction,MAPKK activation,and negative calcium ion transport.Conclusion ADCY9 may be an important prognostic marker of lung adenocarcinoma,and also play an important role in the pathogenesis of gemcitabine-resistance in lung adenocarcinoma.

关 键 词：肺腺癌 腺苷酸环化酶9 耐药 吉西他滨 

分 类 号：R734.2[医药卫生—肿瘤]