基于GEO 数据库数据肝内胆管癌吉西他滨 耐药基因筛选及生物学功能分析.

Objective To screen the gemcitabine-resistant genes in intrahepatic cholangiocarcinoma based on the Gene Expression Omnibus (GEO)database，and to analyze the biological functions of gemcitabine-resistant genes and the relationship between key resistance genes (top ten in MCC value)and tumorigenesis and prognosis. Methods The gemcitabine- resistant intrahepatic cholangiocarcinoma gene set was obtained from the GEO database，and the gemcitabine-resistant genes were analyzed by GEO2R software，and we used the DAVID online tool to perform gene ontology (GO)analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG)analysis of the gemcitabine-resistant genes and then submitted the differential genes to the STRING platform to build a protein-protein interaction network diagram. At the same time，we used the cytohubba plug-in in the Cytoscape software to calculate the top ten genes with MCC value as the key genes. We used Gene Expression Profiling Interactive Analysis (GEPIA)software to analyze the relationship between key genes and the occurrence and prognosis of intrahepatic cholangiocarcinoma. Results A total of 589 gemcitabine-resistant genes were screened out，including 314 up-regulated genes and 275 down-regulated genes. Up-regulated genes were mainly involved in DNA replication，repair，and cell mitosis，etc. ；they affected histone binding，protein binding，DNA binding， protein dimer binding，chromatin binding and other biological functions. Down-regulated genes were mainly involved in angiogenesis， hypoxic response，mitochondrial autophagy，autophagosome assembly，and skeletal muscle cell differentiation； they affected heme binding，voltage-gated ion channels，heparin binding，oxidoreductase and steroid hormone receptor activity，and other biological functions. The key genes in the up-regulated genes were MCM3，CDC45，MCM2， CDC6，MCM4，FEN1，MCM6，PCNA，EXO1，and WDHD1；the key genes in the down-regulated genes were VEGFA， FOS，EGR1，DUSP1，ITGB1，ATF3，GABARAPL1，FOSB，MAP1LC3A，and ULK1. The expression levels of MCM2， MCM6，and CDC45 in the tumor tissues were higher those in the normal tissues (allP <0. 05). The survival rate decreased in patients with high expression of MCM2，MCM6 and CDC45 in the up-regulated key genes，and the survival rate of patients with high expression of activator of transcription 3 (ATF3)in down-regulated genes was higher (both P <0. 05). Conclusions A total of 589 gemcitabine-resistant genes are identified from GSE116118 (314 were up-regulated and 275 were down-regulated). The up-regulated genes mainly involve DNA replication，repair，and biological functions such as cell mitosis，and are enriched in DNA replication，cell cycle，purine pyrimidine metabolism and other signal pathways； down-regulated genes mainly affect angiogenesis，hypoxic response，mitochondrial autophagy，autophagosome assembly and other biological functions，and are enriched in glutamatergic，γ-aminobutyric acid pathway，and Rap1 signaling pathway， etc. The high expression of key genes MCM2，MCM6 and CDC45 are related to the occurrence of tumors，and can lead to poor prognosis of intrahepatic cholangiocarcinoma. [ABSTRACT FROM AUTHOR]