[摘要] 目的: 采用多种生物信息学分析工具，筛选与食管鳞状细胞癌（esophageal squamous cell carcinoma, ESCC）发生发展相关的枢纽基因（Hub gene），并分析其生物学功能。方法：选取GEO食管鳞状细胞癌芯片数据GSE100942 为研究对象，采用GEO2R软件对数据进行处理和分析，筛选差异表达基因，并通过生物信息学工具DAVID、String、Cytoscape 构建差异表达基因的蛋白互作网络并筛选Hub基因；应用GO及KEGG进行生物功能富集分析；同时通过网络工具MiRDB寻找可能调控Hub基因的miRNA，并构建Hub 基因-miRNA调控网络；利用GEPIA在线分析工具对筛选基因的表达和患者生存情况进行验证。结果：分析GSE100942 芯片数据共筛选出1229 个表达差异达2 倍以上及223 个表达差异达4 倍以上的差异基因，以及在食管癌组织中表达均上调的20 个Hub基因；功能富集分析显示这些差异基因主要富集到了癌症相关通路，并主要参与了细胞分裂及有丝核分裂等生物学过程；从Hub基因进一步鉴定了DLGAP5、BUB1B、TPX2、TTK、CDC20、CCNB2、AURKA、DEPDC1 为食管鳞状细胞癌相关的8 个关键Hub基因，他们参与了细胞增殖、细胞周期、信号通路等重要生物学过程。通过构建的miRNA调控网络分析，鉴定了CEP55、ECT2、NEK2、DEPDC1 及NUSAP1 等5 个Hub 基因受该网络高度调控。结论：基因芯片结合生物信息学方法能够有效分析与食管鳞状细胞癌发生发展相关的差异表达基因，筛选出的20 个Hub基因和其中的8 个关键基因可为进一步研究食管鳞状细胞癌发病的分子机制及分子标志物的筛选提供理论指导。

[Abstract] Objective: To screen the Hub genes associated with the occurrence and development of esophageal squamous cell carcinoma (ESCC) and to analyze their biological functions by using various bioinformatics analysis tools. Methods: ESCC chip profile GSE100942 from GEO database was used as study subject; GEO2R tool was used to analyze the data and to screen the differentially expressed genes (DEGs), and the bioinformatics tools (DAVID, String, Cytoscape) were further used to construct protein-protein interaction (PPI) network and identify the key Hub genes. GO and KEGG were used for the biological function enrichment analysis. In the meanwhile, MiRDB was applied to identify the miRNAs that might regulate Hub genes and to construct Hub gene–miRNA network.Importantly, the expression of DEGs and the patient survival were verified by the GEPIA analysis tool. Results: By analyzing GSE100942 database, a total of 1229 DEGs with difference of 2 times and 223 DEGs with difference of 4 times were screened out. In addition, 20 Hub genes, which were all up-regulated in ESCC tissues, were also identified. The functional enrichment analysis showed that these DEGs were mainly enriched in cancer related pathways and involved in cell division and mitotic nuclear division. Among those 20 Hub genes, DLGAP5, BUB1B, TPX2, TTK, CDC20, CCNB2, AURKA and DEPDC1 were identified as 8 key Hub genes that related with ESCC, and involved in many important biological processes, such as cell proliferation, cell cycle and signal pathway. Five Hub genes, CEP55, ECT2, NEK2, DEPDC1 and NUSAP1, were identified to be highly regulated by the miRNA regulatory network.Conclusion: Microarray combined with bioinformatics can effectively analyze the DEGs associated with the occurrence and develop-ment of ESCC. The identification of the 20 Hub genes and the 8 key Hub genes can provide theoretical guidance for further research on the molecular mechanism and molecular marker screening of ESCC.

国家自然科学基金资助项目（NO. 81472335）；河北省医学科学研究重点课题计划项目（No. 20170698）