A Key mRNA-miRNA-lncRNA Competing Endogenous RNA Triple Sub-network Linked to Diagnosis and Prognosis of Hepatocellular Carcinoma

Abstract

Growing evidence has illustrated critical roles of competing endogenous RNA (ceRNA) regulatory network in human cancers including hepatocellular carcinoma. In this study, we aimed to find promising diagnostic and prognostic biomarkers for patients with hepatocellular carcinoma. Three novel unfavorable prognosis-associated genes (CELSR3, GPSM2, and CHEK1) was first identified. We also demonstrated that these genes were significantly upregulated in hepatocellular carcinoma cell lines and tissues. Next, 154 potential miRNAs of CELSR3, GPSM2, and CHEK1 were predicted. CHEK1-hsa-mir-195-5p/hsa-mir-497-5p and GPSM2-hsa-mir-122-5p axes were defined as two key pathways in carcinogenesis of hepatocellular carcinoma by combination of in silico analysis and experimental validation. Subsequently, lncRNAs binding to hsa-mir-195-5p, hsa-mir-497-5p, and hsa-mir-122-5p were predicted via starBase and miRNet databases. After performing expression analysis and survival analysis for these predicted lncRNAs, we showed that nine lncRNAs (SNHG1, SNHG12, LINC00511, HCG18, FGD5-AS1, CERS6-AS1, NUTM2A-AS1, SNHG16, and ASB16-AS1) were markedly increased in hepatocellular carcinoma and their upregulation indicated poor prognosis. Moreover, a similar mRNA-miRNA-lncRNA analysis for six “known” genes (CLEC3B, DNASE1L3, PTTG1, KIF2C, XPO5, and UBE2S) was performed. Subsequently, a comprehensive mRNA-miRNA-lncRNA triple ceRNA network linked to prognosis of patients with hepatocellular carcinoma was established. Moreover, all RNAs in this network exhibited significantly diagnostic values for patients with hepatocellular carcinoma. In summary, the current study constructed a mRNA-miRNA-lncRNA ceRNA network associated with diagnosis and prognosis of hepatocellular carcinoma.