Elevation of Plasminogen Activator Inhibitor-1 Promotes Differentiation of Cancer Stem-Like Cell State by Hepatitis C Virus Infection
- 30 April 2021
- journal article
- research article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 95 (10)
- https://doi.org/10.1128/JVI.02057-20
Abstract
Plasminogen activator inhibitor-1 (PAI-1) is a critical factor that regulates protein synthesis and degradation. 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 (CSCs) 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 miR30c 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 monoclonal antibody (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. This finding implies that manipulation of PAI-1 activity could provide potential therapeutics to prevent the development of HCV-associated chronic liver diseases. IMPORTANCE The progression of chronic liver disease by HCV infection is considered a major risk factor for hepatocellular carcinoma (HCC), one of the major causes of death from cancer. Recent studies have demonstrated that increased CSC properties in HCV-infected hepatocytes are associated with the progression of HCC. Since protein and microRNA (miRNA) production by HCV-infected hepatocytes can play various roles in physiological processes, investigating these factors can potentially lead to new therapeutic targets. However, the mechanism of HCV-associated progression of hepatocytes to CSC remains unclear. Here, we identify the roles of PAI-1 and miR30c in the progression of CSC during HCV infection in hepatocytes. Our data show that increased secretion of PAI-1 following HCV infection promotes this CSC state and activation of AKT. We report that the inhibition of PAI-1 by an miR-30c mimic reduces HCV-associated CSC properties in hepatocytes. Taken together, targeting this interaction of secreted PAI-1 and miR-30c in HCV-infected hepatocytes may provide a potential therapeutic intervention against the progression to chronic liver diseases and HCC.Keywords
Funding Information
- HHS | NIH | OSC | Common Fund (DK122737)
This publication has 76 references indexed in Scilit:
- Hepatitis C Virus Induces Epithelial-Mesenchymal Transition in Primary Human HepatocytesJournal of Virology, 2012
- CD133 expression is associated with poor outcome in neuroblastoma via chemoresistance mediated by the AKT pathwayHistopathology, 2012
- mTORC2 Protein-mediated Protein Kinase B (Akt) Serine 473 Phosphorylation Is Not Required for Akt1 Activity in Human PlateletsPublished by Elsevier BV ,2011
- A Humanized Mouse Model to Study Hepatitis C Virus Infection, Immune Response, and Liver DiseaseGastroenterology, 2011
- Involvement of miR-30c and miR-301a in immediate induction of plasminogen activator inhibitor-1 by placental growth factor in human pulmonary endothelial cellsBiochemical Journal, 2011
- Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker NanogProceedings of the National Academy of Sciences of the United States of America, 2009
- Development of JFH1-based cell culture systems for hepatitis C virus genotype 4a and evidence for cross-genotype neutralizationProceedings of the National Academy of Sciences of the United States of America, 2008
- Robust expansion of human hepatocytes in Fah−/−/Rag2−/−/Il2rg−/− miceNature Biotechnology, 2007
- CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicityInternational Journal of Cancer, 2007
- EpCAM (CD326) finding its role in cancerBritish Journal of Cancer, 2007