Hepatology Highlights

Abstract

Hepatitis C Virus (HCV) infection promotes hepatocyte proliferation, which can progress to hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) involved in signaling pathways for proliferation and apoptosis are altered upon HCV infection. miR-181c was shown to be down-regulated in HCV-infected hepatocytes. Patra et al. now show that miR-181c targets a protein kinase, ataxia-telangiectasia mutated (ATM), which is involved in repairing DNA damage to enhance cell survival. HCV-infected hepatocytes and patient liver tissue exhibited higher ATM and lower miR-181C expression. Enhanced ATM results in protein kinase B (Akt) activation, which then phosphorylates a key cell-cycle regulator, cyclin-dependent kinase-2 (Cdk2). Exogenous expression of miR-181c suppresses Akt activation, down-regulates Cdk2 phosphorylation, and causes cell-cycle arrest in the G 2 phase. Attenuation in cell cycle was associated with apoptosis in hepatocytes. Consistent with these observations, miR-181c promoted apoptosis in xenograft tumors, thereby regressing tumor growth in a xenograft mouse model. The antiproliferative effects of miR-181C suggests a treatment potential for HCV-associated liver disease progression. (Hepat ology 2019;71:780-793).