基于生物信息学方法的食管鳞状细胞癌差异基因筛选和相关生物学特征分析

Bioinformatics analysis of screening of differentially expressed genes and related biological characteristics in esophageal squamous cell carcinoma

目的应用生物信息学方法对食管鳞状细胞癌(以下简称鳞癌)差异基因表达谱进行分析,筛选与食管鳞癌发生、发展相关的关键基因,并寻找食管鳞癌早期诊断和预后的生物标志物。方法从基因表达综合数据库下载食管鳞癌基因芯片数据集GSE26886、GSE77861、GSE100942、GSE20347、GSE23400、GSE38129、GSE17351。首先筛选出各数据集食管鳞癌和正常食管黏膜组织中的差异表达基因,再筛选出7组数据集共同差异表达的关键基因。分别对差异表达关键基因进行基因本体功能、京都基因与基因组百科全书(KEGG)信号通路富集分析。应用Cytoscape软件和分子复合物检测工具构建蛋白质互作网络(PPI)模型,筛选出最关键的主效基因。将主效基因的表达分为高表达组和低表达组,利用Kaplan-Meier数据库分析主效基因与食管鳞癌患者预后的关系。结果在7个数据集中共筛选出626个食管鳞癌差异表达关键基因,包括302个上调基因和324个下调基因。基因本体功能分析表明,差异表达关键基因主要聚集于胶原蛋白结合、细胞周期调控、表皮细胞分化等功能。KEGG信号通路富集分析显示差异表达关键基因主要聚集于细胞外基质-受体交互作用、p53信号通路、花生四烯酸代谢信号通路等。PPI共筛选出5个主效基因,分别为Ⅲ型胶原α1链(COL3A1)、Ⅹ型胶原α1链(COL10A1)、Ⅵ型胶原α3链(COL6A3)、Ⅴ型胶原α2链(COL5A2)、Ⅰ型胶原α1链(COL1A1)。COL3A1、COL10A1、COL6A3、COL5A2、COL1A1在食管鳞癌组织中的表达均高于正常食管黏膜组织。高表达组患者预后较低表达组差。结论食管鳞癌组织和正常黏膜组织存在差异表达基因谱,COL3A1、COL10A1、COL6A3、COL5A2、COL1A1为食管鳞癌发生、发展的关键基因并与患者预后相关,可能是食管鳞癌诊疗新的分子标志物。

Objective To analyze the differentially expressed genes in esophageal squamous cell carcinoma(ESCC)by bioinformatics method,to screen the key genes related to the carcinogenesis and development of ESCC and to find out biomarkers for early diagnosis and prognosis of ESCC.Methods The ESCC microarray datasets GSE26886,GSE77861,GSE100942,GSE20347,GSE23400,GSE38129 and GSE17351 from gene expression omnibus datasets were downloaded.The differentially expressed genes in ESCC and normal esophageal mucosa tissues of each dataset were screened out,and then the common differentially expressed key genes of seven dataset were selected out.After that,the key differentially expressed genes were analyzed by gene ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)pathway.Cytoscape software and molecular complex detection were used for protein-protein interaction network(PPI),and the critical hub genes were screened out.The expression of hub genes was divided into high-expression group and low-expression group.The relationship between hub genes and the prognosis of patients with ESCC was analyzed by Kaplan-Meier database.Results A total of 626 differentially expressed key genes of ESCC were screened out from the seven datasets,including 302 up-regulated genes and 324 down-regulated genes.The results of GO analysis showed that the key differentially expressed genes were mainly involved in collagen binding,regulation of cell cycle and epithelial cell differentiation.The results of KEGG analysis indicated that the differentially expressed genes were focused on extracellular matrix-receptor interaction,p53 signaling pathway and arachidonic acid metabolism signaling pathway.Five hub genes were screened out from PPI,which were collagen typeⅢα1 chain(COL3A1),collagen typeⅩα1 chain(COL10A1),collagen typeⅥα3 chain(COL6A3),collagen typeⅤα2 chain(COL5A2)and collagen typeⅠα1 chain(COL1A1).The expression levels of COL3A1,COL10A1,COL6A3,COL5A2 and COL1A1 in ESCC tissues were higher than those of normal esophageal mucosa tissues.The prognosis of high-expression group was worse than that of low-expression group.Conclusions There are differentially expressed genes profiles between ESCC tissues and normal mucosa tissues.COL3A1,COL10A1,COL6A3,COL5A2 and COL1A1 are key genes in the genesis and development of ESCC and also related to the prognosis of the patients,which may be new molecular markers for the diagnosis and treatment of ESCC.