肝细胞癌组织miR-139水平及其靶基因功能的生物信息学分析

Implication of miR-139 in hepatocellular carcinoma and bioinformatics analysis of its perimentally validated targets genes

目的探讨肝细胞癌(HCC)组织mi R-139水平及其临床意义,并对其潜在的靶基因进行生物信息学分析,为mi R-139在HCC发病机制中的作用研究提供理论基础。方法通过分析国际癌症和肿瘤基因图谱(TCGA)HCC数据库,比较HCC组织与癌旁组织mir-139水平,分析不同临床和病理学(TNM)分期肿瘤组织mir-139水平差异及其与患者生存之间的关系。通过mir Tar Base数据库获取经实验证实的mi R-139靶基因,并利用DAVID生物信息数据库对mi R-139靶基因进行Gene Ontology功能富集分析及Kyoto Encyclopedia of Genes and Genomes信号转导通路富集分析。结果 HCC组织mir-139水平(143.12±117.55)显著低于癌旁组织【(486.48±145.18)g,P<0.01】;随着TNM分期增加,癌组织mir-139水平呈逐渐下降趋势(I期、II期、III期、IV期分别为161±104、124.1±132.5、128±128.5、91.08±77.88,P<0.01);癌组织mir-139水平与TNM分期呈负相关(r=-0.2563,P<0.001);随着肿瘤T分期的增加,癌组织mir-139水平呈逐渐下降趋势(I期、II期、III期、IV期分别为159.8±101.8、121.3±129.2、135.3±131.5、72.57±48.52,P<0.01),且肿瘤组织mir-139水平与HCC T分期呈负相关(r=-0.2586,P<0.001),而与淋巴结转移(N分期)或远处转移(M分期)无显著性相关(均P>0.05);肿瘤组织mir-139水平与患者生存呈正相关,将癌组织mir-139水平由低到高分为4个区间,其中位生存时间分别为16.05 m、16.12 m、24.05 m和24.19 m,组间差异具有统计学意义(Log-rank,P<0.001);mi R-139靶基因功能主要富集于与启动子结合、RNA聚合酶II介导转录和细胞内信号通路传递等分子功能上,相关信号通路主要富集于各种肿瘤相关信号通路、B细胞受体信号通路、Ras信号通路和T细胞受体信号通路传递等。结论 HCC组织mi R-139水平降低,且与患者临床分期和生存呈负相关。mi R-139靶基因功能显著富集于转录调节和肿瘤相关信号通路传递,提示mi R-139在HCC的发生、发展中起到潜在的抑癌基因作用,并可能作为新的治疗靶点和预后标志物。

Objective The aim of this study was to investigate the implication of miR-139 in hepatoceUular carcinoma （HCC） and the bioinformatics analysis of its perimentally validated targets genes. Methods By analyzing the data of HCC in The Cancer Genome Atlas （TCGA） database,we compared the miR-139 levels in HCC tissues and its adjacent liver tissues and analyzed the association between miR-139 levels with pathological stages and survivals of patients. We also retrieved the experimentally validated target genes from the mirTarBase database,and the gene ontology （GO） and the Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis were made. Results Levels of miR-139 in HCC tissues （143.12±117.55） was significantly lower than that in adjacent tissues [（486.48±145.18）,P〈0.01];The patients were stratified into 4 groups based on the levels of mir-139 and the median survival in each groups from low to high were 16.05 m,16.12 m,24.05 m and 24.19 m,respectively,and there was a significant difference among different groups （Log-rank,P〈 0.001）;Go function analysis revealed that miR-139 target genes were mainly regulating binding with promoters and intracellular signaling transduction and KEGG analysis indicated that these genes were mainly involved in cancer-related pathways,B and T cell receptor signaling and Ras signaling pathway. Conclusion miR-139 levels is down-regulated in HCC and is negatively correlated with pathological stages and survival of patients （both P〈0.05）. Bioinformatics analysis suggest that miR-139 contributes to cancer development mainly through regulating gene transcription and cancer-related signaling pathways. The present study indicates that miR-139 plays an inhibitory role in formation and development of HCC.