基于表观遗传因子的肝细胞癌预后模型的构建和验证  

Construction and validation of prognostic model of hepatocellular carcinoma based on epigenetic factors

作　　者：张海航 曾江正[1] 朱旭 孙华茂[1] 杨璐 付裕 卢彦达[1] ZHANG Hai-hang;ZENG Jiang-zheng;ZHU Xu;SUN Hua-mao;YANG Lu;FU Yu;LU Yan-da(Department of Oncology,First Affiliated Hospital of Hainan Medical College,Haikou 570102,China;School of Biomedical Information and Engineering,Hainan Medical College,Haikou 571199,China)

机构地区：[1]海南医学院第一附属医院肿瘤内科,海南海口570102 [2]海南医学院生物医学信息与工程学院,海南海口571199

出　　处：《海南医学院学报》2022年第12期910-920,共11页Journal of Hainan Medical University

基　　金：国家自然科学基金资助项目(81960549)。

摘　　要：目的:探究肝细胞癌(hepatocellular carcinoma,HCC)预后相关的miRNA和表观因子的靶向关系,识别miRNA靶向的表观因子对肝细胞癌预后的潜在影响。方法:通过肿瘤基因组图谱(TCGA)数据库下载全部HCC样本的mRNA和miRNA测序数据,使用R程序对测序数据进行差异分析。将患者生存时间、生存状态与差异表达miRNA表达数据合并,使用单因素和多因素COX风险回归构建miRNA的风险评分模型。预测模型中miRNA靶基因及下载所有的表观因子,并筛选出具有差异表达的表观因子(the differentially expressed epigenetic factors,DEEFs)。然后,建立miRNA靶向DEEFs的调控网络,对网络里的表观因子进行富集分析,构建蛋白质-蛋白质相互作用(PPI)网络和选择网络中的核心基因,最后用KaplanMeier(K-M)法分析表观因子与患者生存预后的关系并予以验证。结果:使用Edge算法鉴定出305个差异表达的miRNA,COX分析最终筛选出hsa-miR-139-5p、hsa-miR-101-3p和hsa-miR-7-5p(miR-139-5p、miR-101-3p和miR-7-5p)作为HCC患者总生存期(overall survival,OS)的预测因子。此外,识别出34个miRNA靶向的DEEFs,其中EZH2、PKM、HJURP和CHEK1对肝细胞癌生存有显著影响。结论:本研究成功建立了肝细胞癌miRNA靶向表观因子的预后模型,并筛选出与肝细胞癌预后显著相关的表观因子。为HCC治疗提供新的潜在的预后生物标志物和治疗靶点,且为HCC后续的基础研究奠定了理论基础。Objective:To explore the targeting relationship between miRNA and epigenetic factors related to the prognosis of hepatocellular carcinoma(HCC),and to identify the potential impact of miRNA targeted epigenetic factors on the prognosis of HCC. Methods:The mRNA and miRNA sequencing data of all HCC samples were downloaded from the tumor Genome Atlas(TCGA)database,and the R program was used to analyze the difference of the sequencing data. The data of survival time,survival status and differential expression of miRNA were combined,and the risk score model of miRNA was constructed by univariate and multivariate Cox regression. The differentially expressed epigenetic factors(deefs)were screened. Then,the regulatory network of miRNA targeting deefs was established,the apparent factors in the network were enriched and analyzed,and the core genes in the protein-protein interaction(PPI)network and selection network were constructed. Finally,the relationship between the apparent factors and the prognosis of patients was analyzed and verified by Kaplan Meier(K-M)method. Results:Using Edge algorithm to identify 305 differentially expressed miRNAs,COX analysis finally screened out hsa-miR-139-5p,hsa-miR-101-3p and hsa-miR-7-5p(miR-139-5p,miR-101-3p and miR-7-5p)as predictors of overall survival(OS)of HCC patients. In addition,34 DEEFs targeted by miRNAs were identified,among which EZH2,PKM,HJURP and CHEK1 had a significant impact on the survival of hepatocellular carcinoma. Conclusion:In this study,we successfully established a prognostic model of hepatocellular carcinoma miRNA-targeted epigenetics,and screened out epigenetic factors that are significantly related to the prognosis of hepatocellular carcinoma. It provides new potential prognostic biomarkers and therapeutic targets for HCC treatment,and lays a theoretical foundation for the follow-up basic research of HCC.

关 键 词：肝细胞癌 表观因子 微小RNA TCGA 

分 类 号：R735.7[医药卫生—肿瘤]