基于生物信息学方法筛选与胃癌预后及5-氟尿嘧啶疗效相关基因

Screening of genes related to the prognosis of gastric cancer and the efficacy of 5-fluorouracil based on bioinformatics method

目的基于生物信息学方法筛选与胃癌预后、5-氟尿嘧啶疗效相关的生物标志物。方法从基因表达综合(GEO)数据库下载基于GPL570平台的GSE54129、GSE79973、GSE51725胃癌数据集。从GEPIA2在线基因表达谱分析工具下载前500例胃癌患者总生存(OS)相关基因。利用GEO2R工具鉴别胃癌组织与癌旁正常组织之间的差异表达基因, 使用STRING数据库建立蛋白质互作网络(PPI)并鉴定关键基因, 通过OmicShare平台进行基因本体(GO)及京都基因与基因组百科全书(KEGG)富集分析。利用Kaplan-Meier Plotter计算关键基因对患者OS的预测价值, 患者样本按基因表达量的最佳临界值分为高表达组和低表达组。结果共筛选出59个差异表达基因, 其中39个上调基因, 20个下调基因。通过PPI分析, 成对同源结构域转录因子2(PITX2)、肝细胞生长因子(HGF)、成纤维细胞生长因子1(FGF1)、转化生长因子β2(TGFB2)、凝血酶反应蛋白1(THBS1)是上调基因PPI中的关键基因。生存分析结果显示, FGF1、HGF、PITX2、TGFB2基因低表达的胃癌患者OS均较好(均P<0.01), THBS1基因低表达的胃癌患者OS较差, 但差异无统计学意义(P>0.05)。采用5-氟尿嘧啶为基础的化疗方案治疗的PITX2基因低表达患者OS较好(P<0.01), THBS1、HGF基因低表达的患者OS较差(P<0.05)。富集分析发现关键基因参与调控TGF-β信号通路、Rap1信号通路、MAPK信号通路、PI3K-Akt信号通路、Hippo信号通路、Ras信号通路、黏着斑通路。结论 FGF1、HGF、PITX2、TGFB2基因表达与胃癌预后相关, PITX2、THBS1、HGF表达与5-氟尿嘧啶疗效相关, 可能作为胃癌患者氟尿嘧啶治疗敏感性的预测标志物。

Objective To screen biomarkers related to the prognosis of gastric cancer and the efficacy of 5-fluorouracil based on the bioinformatics method.Methods Gastric cancer datasets like GSE54129,GSE79973 and GSE51725 based on GPL570 platform were downloaded from Gene Expression Omnibus(GEO)database.Genes related to the overall survival(OS)of the top 500 gastric cancer patients were downloaded from GEPIA2 online gene expression profile.GEO2R was used to identify the differentially expressed genes(DEG)between gastric cancer tissues and adjacent normal tissues,STRING database was used to build protein-protein interaction networks(PPI)and to identify the key genes,the enrichment analysis of gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)was made by using OmicShare.Kaplan-Meier Plotter was used to calculate the value of key genes in predicting the OS of gastric cancer patients.All patients were divided into the high expression group and low expression group according to the optimal cut-off value of gene expression level.Results A total of 59 DEG were screened,including 39 up-regulated genes and 20 down-regulated genes.The key up-regulated genes including homeodomain transcription factors 2(PITX2),hepatocyte growth factor(HGF),fibroblast growth factor 1(FGF1),transforming growth factorβ2(TGFB2),thromobospondin 1(THBS1)were analyzed by using PPI.Survival analysis results showed that the OS of gastric cancer patients with low expression of FGF1,HGF,PITX2 and TGFB2 genes was better(all P<0.01);the OS of gastric cancer patients with low expression of THBS1 gene was poor,while the difference was not statistically significant(P>0.05).The patients with low expression of RIEG1 gene who received 5-fluorouracil-based chemotherapy regimen had the better OS(P<0.01),while those with THBS1 and HGF low expression had the worse OS(P<0.05).It was found that key genes might promote the development of gastric cancer by participating in the regulation of TGF-βsignaling pathway,Rap1 signaling pathway,MAPK signaling pathway,PI3K-Akt signaling pathway,Hippo signaling pathway,Ras signaling pathway and focal adhesion pathway.Conclusions Bioinformatics analysis shows that the expressions of FGF1,HGF,PITX2 and TGFB2 genes are related to the prognosis of gastric cancer,and the expressions of RIEG1,THBS1 and HGF are related to the efficacy of 5-fluorouracil,which may be used as a predictive marker of fluorouracil chemosensitivity in patients with gastric cancer.