焦亡相关基因在胃腺癌中的表达及预后相关性分析

Expression of pyroptosis-related genes in stomach adenocarcinoma and their correlation with prognosis

目的 通过生物信息学方法筛选与胃腺癌(stomach adenocarcinoma,STAD)诊断、预后及免疫浸润相关的焦亡相关基因(pyroptosis-related genes,PRGs)。方法 从癌症基因组图谱(The Cancer Genome Atlas,TCGA)数据库下载数据,利用Networkanalyst数据库筛选在STAD中差异表达的PRGs,通过STRING数据库构建差异表达PRGs的蛋白互作(proteinprotein interaction,PPI)网络。利用Cox回归分析鉴定与STAD患者预后相关的PRGs,并构建列线图展示预后风险模型。利用GSE54129和GSE27342数据集对相关结论进行验证。TIMER数据库分析差异表达PRGs与STAD中免疫细胞浸润的相关性。结果 筛选出STAD中41个差异表达PRGs,其中有36个PRGs表达升高,5个PRGs表达降低(均P<0.05)。在STAD中表达升高且与患者不良预后相关的PRGs有5个,分别是带电多泡体蛋白3(charged multivesicular body protein 3,CHMP3)、焦孔素E(gasdermin E,GSDME)、白介素1α(interleukin 1 alpha,IL1A)、NIMA相关激酶7(NIMA related kinase 7,NEK7)及胎盘生长因子(placental growth factor,PGF;均P<0.05)。多因素Cox回归分析表明,IL1A可作为预测STAD患者总生存率的独立预后危险因素(P<0.05)。在验证数据集GSE54129和GSE27342中分析表明,IL1A在胃癌组织中表达升高(均P<0.05),与TCGA数据库得出的结论一致。功能富集分析提示,STAD中这些PRGs主要参与固有免疫应答、炎症和细胞焦亡等过程。将相关系数│r│>0.5设为筛选标准,发现9个与STAD免疫细胞浸润具有相关性的PRGs,分别是鸟苷酸结合蛋白5(guanylate binding protein 5,GBP5)、载脂蛋白E(apolipoprotein E,APOE)、组织蛋白酶G(cathepsin G,CTSG)、黑色素瘤缺失基因2(absent in melanoma 2,AIM2)、含NLR家族CARD域蛋白4(NLR family CARD domain containing 4,NLRC4)、髓系细胞表达的触发受体2(triggering receptor expressed on myeloid cells 2,TREM2)、Z-DNA结合蛋白质1(Z-DNA binding protein 1,ZBP1)、中性粒细胞弹性蛋白酶(elastase, neutrophil expressed,ELANE)及CD274。这些PRGs主要和STAD中T细胞、调节性T细胞、巨噬细胞以及树突状细胞的浸润具有相关性(均P<0.05)。结论 IL1A可作为STAD患者诊断和预后的潜在标志物,且在STAD中这些PRGs主要参与固有免疫应答的调节以及和多种免疫细胞的浸润相关。

Objective To screen pyroptosis-related genes(PRGs)related to the diagnosis,prognosis and immune infiltration of stom-ach adenocarcinoma(STAD)by bioinformatics analyses.Methods The data were downloaded from The Cancer Genome Atlas(TCGA)database,and the differentially expressed PRGs in STAD were screened using Networkanalyst database.The protein-protein interaction(PPI)network of differentially expressed PRGs was constructed using STRING database.Cox regression analysis was used to identify PRGs related to the prognosis of STAD patients,and a nomogram was constructed to display a prognostic risk model.Data sets GSE54129 and GSE27342 were used to verify the relevant conclusions.TIMER database was used to analyze the correlation between PRGs and immune cell infiltration in STAD.Results Forty-one differentially expressed PRGs were screened out in STAD,including 36 up-regulated PRGs and 5 down-regulated PRGs(all P<0.05).Five overexpressed PRGs were related to the poor prognosis of STAD patients,including charged multivesicular body protein 3(CHMP3),gasdermin E(GSDME),interleukin 1 alpha(IL1A),NIMA related kinase 7(NEK7),and placen-tal growth factor(PGF,all P<0.05).Multivariate Cox regression analysis showed that IL1A was an independent prognostic factor for the overall survival of STAD patients(P<0.05).Analysis in validation data sets GSE54129 and GSE27342 showed that the expression of IL1A was increased in gastric cancer tissues,which was consistent with the conclusion obtained from the TCGA database.Functional enrichment analysis suggested that these PRGs were mainly involved in innate immune response,inflammatory response and pyroptosis in STAD.Ac-cording to the correlation coefficient|r|>0.5,nine PRGs were found to be associated with immune cell infiltration in STAD,including gua-nylate binding protein 5(GBP5),apolipoprotein E(APOE),cathepsin G(CTSG),absent in melanoma 2(AIM2),NLR family CARD domain containing 4(NLRC4),triggering receptor expressed on myeloid cells 2(TREM2),Z-DNA binding protein 1(ZBP1),CD274,and elastase,neutrophil expressed(ELANE).The results showed that these PRGs were significantly associated with the infiltration of T cells,regulatory T cells,macrophages and dendritic cells in STAD(all P<0.05).Conclusions IL1A can be used as a potential marker for the diagnosis and prognosis of STAD patients,and these PRGs are mainly involved in the regulation of innate immune response and were associated with the infiltration of many immune cells.