Elevation of Plasminogen Activator Inhibitor-1 promotes differentiation of Cancer Stem-like Cell state by Hepatitis C Virus infection.

Plasminogen activator inhibitor-1 (PAI-1) is a critical factor that regulates protein synthesis and degradation. The increased PAI-1 levels are detectable in the serum of patients with chronic hepatitis C virus (HCV) liver disease. The differentiation state and motility of HCV-induced cancer stem-like cells (CSC) play a major role in severe liver disease progression. However, the role of PAI-1 in the pathological process of chronic liver diseases remains unknown. In this study, we determined how PAI-1 affects the differentiation of CSC state in hepatocytes upon HCV infection. We found that HCV infection induced the expression of PAI-1 while decreasing miR-30c expression in Huh7.5.1 cells. Similar results were obtained from isolated hepatocytes from humanized liver mice after HCV infection. Moreover, decreased miR-30c expression in HCV-infected hepatocytes was associated with the increased levels of PAI-1 mRNA and protein. Notably, the increased PAI-1 levels resulted in the activation of Protein Kinase B/AKT, a major mediator of cell proliferation, in HCV-infected hepatocytes along with the increased expression of CSC markers such as Human Differentiated Protein (CD) 133, Epithelial cell adhesion molecule (EpCAM), Octamer 4 (Oct4), Nanog, Cyclin D1, and MYC. Moreover, blockade of PAI-1 activity by miR-30c mimic and anti-PAI-1 mAb abrogated the AKT activation with decreased expression of CSC markers. Our findings suggest that HCV infection induces the CSC state via PAI-1-mediated AKT activation in hepatocytes. It implicates that the manipulation of PAI-1 activity could provide potential therapeutics to prevent the development of HCV-associated chronic liver diseases.