基于生物信息学技术筛选并分析激素受体阳性乳腺癌内分泌治疗耐药相关基因  

The genes of endocrine drug resistance in hormone receptor positive breast cancer were screened and analyzed based on bioinformatics

作　　者：杜松丽 樊莉 陈茂山[2] 周恋 华帮江 杨宏伟 Du Songli;Fan Li;Chen Maoshan;Zhou Lian;Hua Bangjiang;Yang Hongwei(School of Graduate,Zunyi Medical University,Zunyi Guizhou 563099,China;Department of Breast and Thyroid Surgery,Suining Central Hospital,Suining Sichuan 629000,China)

机构地区：[1]遵义医科大学研究生院,贵州遵义563099 [2]遂宁市中心医院乳腺甲状腺外科,四川遂宁629000

出　　处：《遵义医科大学学报》2023年第1期65-72,共8页Journal of Zunyi Medical University

基　　金：超声医学工程国家重点实验室面上项目(NO:2020KFA3011)。

摘　　要：目的应用生物信息学方法分析激素受体阳性乳腺癌基因芯片数据,筛选内分泌治疗(ET)耐药组与敏感组间差异表达基因(DEGs),探索内分泌治疗耐药可能相关的信号通路。方法在基因表达汇编(GEO)数据库选取GSE67916、GSE51390基因芯片数据,利用GEO2R分析芯片集ET耐药和敏感组间的DEGs,利用Venn diagram筛选两个芯片集中共同表达的DEGs。通过STRING数据库及Cytoscape 3.8.2软件构建DEGs对应蛋白间的互作网络(PPI),筛选出前20个关键蛋白,应用DAVID数据库对20个关键蛋白对应基因进行GO分析及KEGG分析。应用Kaplan-Meier plotter数据库对20个关键基因进行预后分析,选取本中心乳腺癌ET敏感和耐药患者的病理标本,采用免疫组织化学法(IHC)检查关键DEGs基因相应蛋白的表达,验证蛋白表达情况与ET耐药的关系。结果从两个芯片集中筛选出共同表达DEGs 184个,其中上调基因68个、下调基因116个。以构建PPI网络分析获得的关联性最强的前20个基因为本研究的主要对象。使用Kaplan-Meier Plotter在线数据库分析20个基因与激素受体阳性乳腺癌无复发生存(Recurrence-free survival,RFS)的关系,结果显示11个基因的表达与乳腺癌RFS相关(P均<0.05),分别是PTPN11、SDC1、CD24、ITPR1、GATA3、PLCG2、ESR1、PGR、ERBB4、TP53及FGFR2。本中心数据库中按1∶1随机选取ET耐药和敏感病例及对应病理标本(21对),IHC检测20个蛋白,结果显示,ERBB4、PTPN11、GATA3、TP53、PGR、PLCG2、SDC1等7个DRGs在激素受体阳性的乳腺癌组织中显著高表达。结论SDC1等7个免疫相关基因可能成为预测激素受体阳性乳腺癌患者发生内分泌治疗耐药的生物标志物,为临床诊疗提供新策略。Objective To analyze hormone receptor-positive breast cancer gene chip data,to screen differentially expressed genes(DEGs)between the endocrine therapy(ET)resistance and sensitive groups,and to explore the possible signaling pathways related to endocrine therapy resistance.Methods GSE67916 and GSE51390 were selected from Gene Expression Omnibus(GEO)database,GEO2R was used to analyze the DEGs between ET resistance and sensitivity groups,and the co-expressed DEGs in the two microarrays was screened by Venn Diagram.Protein-protein interaction(PPI)network was constructed by STRING database and Cytoscape 3.8.2 software,and the top 20 key protein/genes were analyzed by Gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)using DAVID database.The prognosis of 20 key genes was analyzed by the Kaplan-Meier Plotter online database.Pathological samples of breast cancer patients with ET sensitivity and resistance were selected in our center,and the expression of key proteins was examined by the immunohistochemistry.Results A total of 184 co-expressed DEGs were screened from the two microarray sets,including 68 up-regulated and 116 down-regulated genes.The PPI network identified top 20 protein/genes.Recurrence-Free Survival(RFS)analysis of 20 genes were performed using the Kaplan-Meier Plotter online database.The result showed that the expression of 11 genes(PTPN11,SDC1,CD24,ITPR1,GATA3,PLCG2,ESR1,PGR,ERBB4,TP53 and FGFR2)was associated with RFS of breast cancer(all P<0.05).ET resistant and sensitive cases and corresponding pathological specimens(21 pairs)were randomly selected in our center at a 1∶1 ratio,and 20 proteins were detected by IHC.The results showed that 7 proteins(ERBB4,PTPN11,GATA3,TP53,PGR,PLCG2 and SDC1)were significantly overexpressed in hormone receptor-positive breast cancer tissues.Conclusion SDC1 and other genes maybe biomarkers for predicting endocrine therapy resistance in patients with hormone receptor-positive breast cancer,providing new strategies for clinical diagnosis and treatment.

关 键 词：乳腺癌 激素受体 内分泌治疗 耐药 基因 生物信息学 

分 类 号：R737.9[医药卫生—肿瘤]