恶性胸膜间皮瘤中差异表达基因的预后意义及免疫细胞浸润分析

Prognostic significance and immune cell infiltration analysis of differentially expressed genes in malignant pleural mesothelioma

目的基于生物信息学方法挖掘分析恶性胸膜间皮瘤(MPM)的差异表达基因,研究其在MPM中的预后价值及其在免疫治疗中的潜在作用。方法于2022年1月,从GEO数据库下载数据集GSE51024,获得MPM(55例)和正常组织(41例)样本。利用R软件结合HMDD和miRNet数据库筛选MPM相关差异基因并确定共表达基因。对共表达基因进行富集和功能注释,使用STRING数据库和Cytoscape软件构建蛋白质-蛋白质相互作用(PPI)网络并确定关键基因。利用TRRUST、GEPIA数据库预测关键基因的转录因子及预后生存分析。使用TIMER分析关键基因和免疫细胞浸润程度的相关性。结果共获得435个共表达基因,主要富集于细胞外基质组织、细胞黏附分子信号通路。结合PPI和TRRUST数据库,确定7个MPM预后相关的关键基因,其中细胞周期蛋白20(CDC20)、细胞周期检测点激酶1(CHEK1)、Zeste基因增强子同源物2(EZH2)、核糖核苷酸还原酶亚基M2(RRM2)、拓扑异构酶2A(TOP2A)、泛素样含植物同源结构域和环指域1(UHRF1)在MPM中的表达上调,周期调节蛋白A1(CCNA1)表达下调;CCNA1、CDC20、CHEK1、EZH2、RRM2、TOP2A、UHRF1基因表达与MPM总体生存率有明显关联(P<0.05)。CDC20、CHEK1、EZH2、RRM2、TOP2A基因表达与B细胞、树突状细胞均呈正相关(P<0.05),与中性粒细胞均呈负相关(P<0.05)。结论CCNA1、CDC20、CHEK1、EZH2、RRM2、TOP2A、UHRF1可能是MPM患者潜在的预后标志物,其表达可能与MPM肿瘤免疫相关。

Objective To explore and analyze differential expressed genes in malignant pleural mesothelioma(MPM)by bioinformatics method,and to study their prognostic value in MPM and their potential role in immunotherapy.Methods In January 2022,the dataset GSE51024 was downloaded from the GEO database,and MPM(55 cases)and normal tissue(41 cases)samples were obtained.Using R software and HMDD and miRNet database,MPM-related differential genes were screened and co-expressed genes were identified.Co-expressed genes were enriched and functionally annotated,and protein-protein interaction(PPI)networks were constructed and key genes were identified using the STRING database and Cytoscape software.TRRUST and GEPIA databases were used to predict transcription factors of key genes and to analyze prognosis and survival.The correlation between key genes and the degree of infiltration of immune cells was analyzed using TIMER.Results A total of 435 co-expressed genes were obtained,which were mainly concentrated in the extracellular matrix tissue and the signaling pathways of cell adhesion molecules.Combined with PPI and TRRUST database,seven key MPM prognostic genes were identified.Among them,cyclin 20(CDC20),cell cycle checkpoint kinase 1(CHEK1),enhancer of Zeste homolog 2(EZH2),ribonucleotide reductase subunit M2(RRM2),topoisomerase 2A(TOP2A),ubiquitin like plant homeodomain and ring finger domain 1(UHRF1)were significantly up-regulated in MPM,while cyclin A1(CCNA1)was significantly down-regulated.The expressions of CCNA1,CDC20,CHEK1,EZH2,RRM2,TOP2A and UHRF1 genes were significantly associated with MPM overall survival(P<0.05).The expressions of CDC20,CHEK1,EZH2,RRM2 and TOP2A genes were positively correlated with B cells and dendritic cells(P<0.05),and negatively correlated with neutrophils(P<0.05).Conclusion CCNA1,CDC20,CHEK1,EZH2,RRM2,TOP2A and UHRF1 may be potential prognostic markers in MPM patients,and their expressions may be related to MPM tumor immunity.