Identification of prognostic miRNA-mRNA regulatory network in the progression of HCV-associated cirrhosis to hepatocellular carcinoma.

Background: Long-term hepatitis C virus (HCV) infection is strongly associated with hepatocellular carcinoma (HCC), yet the mechanisms of the progression process remain unclear. The research is aiming to establish a crucial prognostic model that indicates the risk of HCV-associated cirrhosis evolving into HCC.

Methods: Differentially expressed microRNAs (DE-miRNAs) and differentially expressed genes (DEGs) between HCV-associated cirrhosis and HCC were screened from the GSE40744 and GSE6764 datasets, respectively. Downstream target genes of DE-miRNAs were predicted by the miRNet tool and then overlapped with the DEGs to select intersection genes. The GSE15654 was downloaded to establish a prognostic model. Expression levels of risk genes and their corresponding miRNAs were measured in liver tissues of clinical patients. HCC cell lines with UHRF1 knockdown or overexpression were assayed for cell proliferation and migration.

Results: Thirty-nine DE-miRNAs and 796 DEGs are identified between HCV-associated cirrhosis and HCC. Main intersection genes and their corresponding miRNAs constitute a miRNA-mRNA regulatory network. PABPC1 (Polyadenylate-binding protein 1), SLC2A9 (solute carrier gene family 2, member 9), and UHRF1 (ubiquitin-like with PHD and ring finger domains 1) form a prognostic model indicating the risk of HCC development among HCV-associated cirrhosis. The genetic mutations of PABPC1, SLC2A9, and UHRF1 in HCC patients are 9%, 0.8%, and 0.6%, respectively. Compared to that in HCV-associated cirrhosis, the expression levels of PABPC1 and UHRF1 are higher while the expression level of SLC2A9 is lower in clinical HCV-associated HCC samples. UHRF1 enhances the proliferation and migration ability of HCC cells.

Conclusions: PABPC1, SLC2A9, and UHRF1 and their corresponding miRNAs are involved in the evolution process of HCV-associated cirrhosis into malignant HCC. UHRF1 serves as an oncogene that promotes the proliferation and migration of HCC cells.