Construction of Novel mRNA-miRNA-lncRNA Regulatory Networks Associated with Prognosis of HCV Related HCC

Abstract

Background: Infection with hepatitis C virus (HCV) can cause hepatic fibrosis and cirrhosis, thereby significantly increasing the risk of HCC development. Many prior studies have shown that oncogenesis and cancer progression are governed by competing endogenous RNA (ceRNA) networks composed of long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs. As such, we herein sought to identify and evaluate the prognostic relevance of novel ceRNA network related to HCC associated with HCV. Methods: Differentially expressed genes (DEGs) in the GSE140845 Gene Expression Omnibus (GEO) dataset were identified using NetworkAnalyst, and were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Gene, Genome (KEGG) pathway, and Reactome analyses. In addition, a protein-protein interaction (PPI) network was generated, and key hub genes were detected. Hub gene expression levels, as well as those of their upstream lncRNAs and miRNAs and associated survival analyses were conducted using appropriate bioinformatics databases. Predicted target relationships were additionally used to establish putative ceRNA networks for HCV-related HCC. Results: 372 and 360 upregulated and downregulated significant DEGs were identified, respectively. Functional enrichment analyses suggested that DE-mRNAs were associated with nuclear division, the cell cycle, and ATPase activity. The top 11 genes with the greatest degree of connectivity among these DE-mRNAs were selected for subsequent prognostic evaluation. The differential expression of six of these candidate mRNAs (BUB1, BUB1B, CDC20, CDC45, CDK1, NDC80) in liver tissue was validated. After further analyses of the expression and prognostic relevance of the miRNAs and lncRNAs predicted to lie upstream of these DE-mRNAs, we identified 22 miRNAs and 4 lncRNAs significantly associated with poorer-HCV-related HCC prognosis. By combining the results of these analyses, we also identified the BUB1-hsa-miR-193a-3p-MALAT1 ceRNA sub-network as being related to the survival of these patients. Conclusion: This study providing novel insights into the mRNA-miRNA-lncRNA ceRNA network and reveals potential lncRNA biomarkers in HCV related HCC.