非肝硬化乙型肝炎病毒相关肝细胞癌的转录组测序及其对患者生存的影响

Transcriptome sequencing and survival analysis of noncirrhotic hepatitis B viral(HBV)-related hepatocellular carcinoma

目的通过转录组测序以及生物信息学分析探讨非肝硬化乙型肝炎病毒(hepatitis B viral,HBV)相关肝细胞癌的转录特征及与患者生存的关系。方法通过转录组测序获得非肝硬化HBV相关肝细胞癌(hepatocellular carcinoma,HCC)的差异表达基因;利用基因本体(gene ontology,GO)和京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)数据库富集分析获得差异表达基因涉及的生物功能过程及信号通路;通过基因-基因功能相互作用网络分析获得关键基因;利用癌症基因图谱(the cancer genome atlas,TCGA)数据库肝癌队列对关键基因进行生存预后分析。结果共发现上调差异基因3672个,下调差异基因2715个。GO功能富集分析主要涉及细胞分化、DNA复制、DNA修复、炎症反应免疫应答、细胞黏附等。KEGG通路富集主要包括细胞周期、氧化磷酸化、p53信号通路、肿瘤坏死因子(tumor necrosis factor,TNF)信号通路和核因子κB(nuclear factor kappa-B,NF-κB)信号通路等。其中丝裂原活化蛋白激酶3(mitogen-activated protein kinase 3,MAPK3)、Ras相关C3肉毒毒素底物1(ras-related C3 cotulinum toxin substrate 1,RAC1)、磷脂酶Cβ1(phospholipase C beta 1,PLCβ1)、连环蛋白β1(catenin beta 1,CTNNβ1)、非转移性细胞1(non-metastatic cells 1,NME1)基因和非转移性细胞6(non-metastatic cells 6,NME6)基因高表达与肝癌患者预后不良相关(P<0.05);FYN、细胞色素P450(cytochrome P450,CYP)2C8和CYP2C9低表达与肝癌患者预后不良有关(P<0.05)。结论非肝硬化HBV相关肝细胞癌发生涉及多个生物学过程和信号通路的改变,与肝癌患者的生存预后相关的关键基因为理解非肝硬化HBV相关HCC发生机制提供新线索。

Objective Transcriptome sequencing and bioinformatics analysis were used to explore the transcriptional characteristics and survival analysis of non-cirrhotic hepatitis B viral(HBV)-related hepatocellular carcinoma(HCC).Methods The differentially expressed genes in non-cirrhotic HBV-related HCC were obtained by transcriptome sequencing.The biological functional processes and signaling pathways involved in the differentially expressed genes were obtained by gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis.The key genes were obtained by gene-gene function interaction network analysis,and the key genes were analyzed for survival prognosis using the cancer genome atlas(TCGA)database’s HCC cohort.Results A total of 3672 up-regulated differential genes and 2715 down-regulated differential genes were identified.The GO functional enrichment analysis mainly involved cell differentiation,DNA replication,DNA repair,inflammation response,immune response,cell adhesion,etc,while the KEGG pathway enrichment mainly included cell cycle,oxidative phosphorylation,p53 signaling pathway,tumor necrosis factor(TNF)signaling pathway,and nuclear factor kappa-B(NF-κB)signaling pathway.Among them,high expression of mitogen-activated protein kinase 3(MAPK3),ras-related C3 cotulinum toxin substrate 1(RAC1),phospholipase C beta 1(PLCβ1),catenin beta 1(CTNNβ1),non-metastatic cells 1(NME1),and non-metastatic cells 6(NME6)was associated with poor prognosis in HCC patients(P<0.05),while low expression of FYN,cytochrome P4502C8(CYP2C8),and cytochrome P4502C9(CYP2C9)was associated with poor prognosis in HCC patients(P<0.05).Conclusions Non-cirrhotic HBV-related HCC involves multiple biological processes and alterations in signaling pathways,and the key genes related to the survival and prognosis of HCC patients provide new clues for understanding the mechanism of HBV-related HCC in non-cirrhosis patients.