基于生物信息学分析miRNA-195-5p在肝癌中的表达及其临床意义

Expression of miRNA-195-5p in Hepatocellular Carcinoma and Its Clinical Significance: Evidence from Bioinformatics Analysis

为了研究miRNA-195-5p在肝癌(liver hepatocellular carcinoma, LIHC)中的表达及对预后的影响,并对其潜在靶基因进行生物学信息学分析,评估miRNA-195-5p在LIHC中的临床意义和诊断价值,本文利用癌症基因组图谱(TCGA)数据库分析miRNA-195-5p在肝癌组织中的表达;利用Kaplan-Meier plotter数据库分析miRNA-195与肝癌患者预后的相关性;利用miRWalk 2.0数据库获取预测的与实验数据支持的miRNA-195-5p的靶基因,同时采用DAVID 6.8数据库对靶基因进行GO和KEGG富集分析,以Cytoscape 3.6.1软件构建靶基因蛋白质-蛋白质相互作用(PPI)网络并筛选PPI网络中的核心基因;通过公开访问的数据库进一步验证筛选出的核心基因。TCGA数据库分析结果显示, miRNA-195-5p在肝癌组织中的表达水平显著低于正常组织。Kaplan-Meier生存分析显示, miRNA-195低表达LIHC患者的总生存时间明显低于高表达患者。GO分析显示,miRNA-195-5p的靶基因主要显著富集到蛋白质磷酸化、RNA聚合酶Ⅱ启动子转录的正调节、RNA聚合酶Ⅱ启动子转录的负调节等生物学过程。KEGG分析显示, miRNA-195-5p的靶基因显著富集于癌症相关通路。miRNA-195-5p潜在靶基因所编码蛋白质之间存在复杂的相互作用,其中POLR2A、MIB1、MAPK3、ACACA、ASH1L以及MAP3K3是PPI网络中的核心基因。6个核心基因中,仅MAPK3的蛋白质与m RNA表达水平在LIHC组织中均显著上调。Kaplan-Meier生存分析进一步显示, MAPK3 m RNA水平升高预示LIHC患者总生存时间缩短。以上生物信息学分析结果初步表明, miRNA-195-5p表达下调在肝癌相关的生物学过程中起到重要调控作用,可能与其潜在靶基因MAPK3表达上调有关,这为肝癌的生物标志物研究提供了线索。

To evaluate the clinical significance and diagnostic value of miRNA-195-5p in liver hepatocellu-lar carcinoma (LIHC), the expression and prognostic value of miRNA-195-5p and the network of its target genes in LIHC were analyzed using bioinformatics tools. The expression profiles in LIHC tissues were analyzed using The Cancer Genome Atlas (TCGA) database. The relationship between miRNA-195 and the survival of LIHC was analyzed using the Kaplan-Meier plotter online tools. miRWalk 2.0 with 12 online target gene prediction databases was used to attain the prospective target genes. Gene Ontology (GO) analysis, enrichment of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and protein-protein interaction (PPI) analysis were performed to provide an overview of the functions of miRNA-195-5p in LIHC. A set of publicly accessible databases were used for validation of hub genes. Based on miRNA-Seq data in the TCGA database, miRNA-195-5p was shown to be downregulated in LIHC tissues. Low miRNA-195 expression was associated with an unfavorable overall survival of LIHC. Protein phosphorylation, positive regulation of transcription from RNA polymerase Ⅱ promoter and negative regulation of transcription from RNA polymerase Ⅱ promoter were highlighted as the most enriched GO terms. KEGG analysis indicated that these genes were mainly involved in cancer-related pathways. Six genes, POLR2A, MIB1, MAPK3, ACACA, ASH1L and MAP3K3, were defined as hub genes in the PPI network. Among them, only MAPK3 showed an up-regulated pattern in both mRNA and protein levels. Furthermore, high MAPK3 expression was associated with an unfavorable overall survival of LIHC. The bioinformatics analysis suggests that down-regulated miRNA-195-5p may play an essential regulatory role in the biological process of LIHC, which may be associated with expression upregulation of its target gene MAPK3. The results provide clues for studying potential diagnostic biomarkers of LIHC.