摘要
背景肝细胞癌(hepatocellular carcinoma,HCC)是消化系统常见恶性肿瘤,预后较差.本文拟采用生物信息学方法探讨CCNA2基因在HCC中的表达情况,及其作为HCC患者预后分子标志物的可行性.同时,采用免疫组织化学法对CCNA2生物信息分析结果进行验证.目的探讨CCNA2在HCC中的表达,相关信号通路及与患者预后关系.方法应用生物信息分析工具比对TCGA数据库中CCNA2基因mRNA在HCC组织和癌旁组织中表达水平;在STRING数据库中构建CCNA2蛋白-蛋白相互作用网络,并对相关蛋白功能和KEGG信号通路进行富集.根据CCNA2表达水平分为高低表达组,比较CCNA2高低组患者总生存(overall survival,OS)和无疾病进展生存(disease free survival,DFS)是否不同.回顾性分析72例手术治疗的HCC患者,采用免疫组织化学法检测患者癌组织中CCNA2蛋白表达水平与患者临床病理特征的关系,对生物信息分析结果进行验证.结果在HCC中,CCNA2中mRNA表达水平明显高于癌旁正常肝组织;与CCNA2蛋白相互作用较为紧密的蛋白10个,蛋白间相互作用关系edge=50,区域聚类指数为0.931,与CCNA2蛋白相互作用较为紧密的10蛋白相互作用网络富集显著(P<0.05);TOP2基因mRNA与CCNA2正向相关表达(r=0.85,P<0.05),而CCL14基因与CCNA2负相关表达(r=-0.54,P<0.05).CCNA2基因相关信号通路主要富集于细胞周期、病毒致癌、乙型肝炎、p53信号通路和PI3K-Akt信号通路等.预后分析提示CCNA2基因mRNA高表达患者OS(HR=1.7,P=0.0037)和DFS低于低表达组(HR=1.6,P=0.0037).免疫组化显示CCNA2蛋白在HCC患者癌组织中的高表达率为34.7%(25/72).CCNA2蛋白高表达与HCC患者肿瘤直径(P<0.05)、DC浸润(P<0.05)、术后2年复发/转移(P<0.05)有关.结论CCNA2基因在HCC患者癌组织中表达水平上调,并可作为HCC预后不良的分子标记物.
BACKGROUND Hepatocellular carcinoma(HCC)is one of the most diagnosed malignant carcinomas of the digestive system with a poor prognosis.In this study,the expression of CCNA2 gene expression in HCC was investigated by bioinformatics analysis and the feasibility of CCNA2 gene as a molecular marker for prognosis in HCC was assessed.The results of bioinformatics analysis were verified by immunohistochemistry assay.AIM To investigate the expression of CCNA2 in HCC,related signal pathways,and its relationship with prognosis.METHODS The expression levels of CCNA2 mRNA in HCC and paracancerous tissues were compared based on the TCCA database.CCNA2 protein interaction network was constructed based on the String database,and the related protein function and KEGG signal pathways were enriched.According to the expression level of CCNA2,the patients were divided into high and low expression groups,and the difference in overall survival(OS)and disease free survival(DFS)was compared between the two groups.The relationship between the expression of CCNA2 protein analyzed by immunohistochemistry and the clinicopathological features of 72 patients with HCC who underwent surgical treatment was analyzed.RESULTS The expression level of CCNA2 mRNA was significantly higher in HCC than in normal liver tissues.There are ten proteins that have a close interaction with CCNA2 protein,with edge=50,and the regional clustering index is 0.931.The interaction network of the ten proteins that have a close interaction with CCNA2 protein was significantly enriched(P<0.05).The expression of TOP2 mRNA was positively correlated with CCNA2 expression(r=0.85,P<0.05),while CCL14 expression was negatively correlated with CCNA2 expression(r=-0.54,P<0.05).CCNA2 gene related signaling pathways are mainly enriched in cell cycle,viral carcinogenesis,hepatitis B,p53 signaling pathway,and PI3K-Akt signaling pathway.The prognosis analysis indicated that the OS(HR=1.7,P=0.0037)and DFS rates were significantly lower in the high expression group than in the low expression group(HR=1.6,P=0.0037).Immunohistochemistry showed that the high expression rate of CCNA2 in HCC was 34.7%(25/72).High expression of CCNA2 protein was significantly associated with tumor diameter(P<0.05),DC infiltration(P<0.05),and recurrence/metastasis 2 years after operation(P<0.05).CONCLUSION CCNA2 gene is up-regulated in HCC,which can be used as a molecular marker for poor prognosis in HCC.
作者
杨结
刘树业
刘运德
Jie Yang;Shu-Ye Liu;Yun-De Liu(Clinical Laboratory,Tianjin Third Central Hospital Affiliated To Tianjin Medical University,Tianjin Institute of Hepatobiliary Disease,Tianjin Key Laboratory of Artificial Cell,Artificial Cell Engineering Technology Research Center of Public Health Ministry,Tianjin 300170,China;School of Medical Laboratory,Tianjin Medical University,Tianjin 300170,China)
出处
《世界华人消化杂志》
CAS
2019年第24期1490-1501,共12页
World Chinese Journal of Digestology
