Abstract
Osteopontin (OPN) is involved in cell proliferation, migration, inflammation, and tumor progression in various tissues. OPN induces stemness by interacting with CD44, but the functional relevance of OPN-mediated interferon (IFN) signaling and hepatitis C virus (HCV) replication in stem cell populations remains unclear. In this study, we investigated the effect of OPN on HCV replication and IFN signaling in cancer stem cells (CSCs) positive for epithelial cell adhesion molecule (EpCAM) and CD44. We show that the EpCAM+/CD44+ CSCs show marked HCV replication when compared to EpCAM−/CD44− cells. In addition, OPN significantly enhances this HCV replication in EpCAM+/CD44+ CSCs and markedly suppresses IFN-stimulated gene expression. The GSK-3β inhibitor BIO increases the EpCAM+/CD44+ CSC population and OPN expression and impairs IFN signaling via STAT1 degradation. Taken together, our data suggest that OPN enhances HCV replication in the EpCAM+/CD44+ CSCs, while it also negatively regulates the IFN signaling pathway via inhibition of STAT1 phosphorylation and degradation. Therefore, OPN may represent a novel therapeutic target for treating HCV-related hepatocellular carcinoma.
Highlights
OPN-mediated interferon (IFN) signaling and hepatitis C virus (HCV) replication in stem cell populations remains unclear
HCV replication is increased in epithelial cell adhesion molecule (EpCAM)+/CD44+ cancer stem cells (CSCs)
These results suggest that BIO augments the EpCAM+/CD44+ CSC population and increases HCV replication though STAT1 degradation
Summary
OPN-mediated interferon (IFN) signaling and hepatitis C virus (HCV) replication in stem cell populations remains unclear. We investigated the effect of OPN on HCV replication and IFN signaling in cancer stem cells (CSCs) positive for epithelial cell adhesion molecule (EpCAM) and CD44. OPN significantly enhances this HCV replication in EpCAM+/CD44+ CSCs and markedly suppresses IFN-stimulated gene expression. Our data suggest that OPN enhances HCV replication in the EpCAM+/CD44+ CSCs, while it negatively regulates the IFN signaling pathway via inhibition of STAT1 phosphorylation and degradation. Hepatitis C virus (HCV) infection, as the major cause of hepatocellular carcinoma (HCC)[1,2,3], was estimated to be responsible for 745,000 deaths in 20124. In addition to these interactions with integrins, OPN reportedly interacts with CD4417
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