Hepatitis C Virus Core Protein Modulates Endoglin (CD105) Signaling Pathway for Liver Pathogenesis

Abstract

Endoglin is part of the TGF-β receptor complex and has a crucial role in fibrogenesis and angiogenesis. It is also an important protein for tumor growth, survival, and cancer cell metastasis. In a previous study, we have shown that hepatitis C virus (HCV) infection induces epithelial-mesenchymal transition (EMT) state and cancer stem-like cell (CSC) properties in human hepatocytes. Our array data suggested that endoglin (CD105) mRNA is significantly upregulated in HCV-associated CSCs. In this study, we have observed increased endoglin expression on the cell surface of an HCV core-expressing hepatocellular carcinoma (HepG2) cell line or immortalized human hepatocytes (IHH) and activation of its downstream signaling molecules. The status of phospho-SMAD1/5 and the expression of inhibitor of DNA binding protein 1 (ID1) were upregulated in HCV-infected cells or viral core gene-transfected cells. Additionally, we observed upregulation of endoglin/ID1 mRNA expression in chronic HCV patient liver biopsy samples. CSC generation by HCV core protein was dependent on the endoglin signaling pathway using activin receptor-like kinase 1 (ALK1) Fc blocking peptide and endoglin small interfering RNA (siRNA). Further, follow-up from analysis suggested that the antiapoptosis Bcl2 protein, proliferation-related cyclin D1 protein, and CSC-associated Hes1, Notch1, Nanog, and Sox2 proteins are enhanced during infection or ectopic expression of HCV core protein. Endoglin plays a crucial role in fibrogenesis and angiogenesis and is an important protein for tumor growth, survival, and cancer cell metastasis. Endoglin enhances ALK1-SMAD1/5 signaling in different cell types, leading to increased proliferation and migration responses. We have observed endoglin expression on the HCV core-expressing cell surface of human hepatocyte origin and activation of phospho-SMAD1/5 and ID1 downstream signaling molecules. ID1 protein plays a role in CSC properties, and we found that this pathway is important for antiapoptotic and cell proliferation signaling. Blocking of endoglin-ALK1-SMAD1/5 might be a good candidate for therapy for liver cancer stem cells together with liver cirrhosis.

Relationships between serum selenium and zinc concentrations versus profibrotic and proangiogenic cytokines (FGF-19 and endoglin) in patients with alcoholic liver cirrhosis

“…Furthermore, a positive correlation has been observed between the concentration of ENG and α-fetoprotein [8]. Kwan et al have described a potential role of ENG in initiation of fibrosis in patients with liver cirrhosis in the course of HCV infection [29]. ENG is an accessory receptor for transforming growth factor-β involved in the pathogenesis of fibrosis.…”

Inhibitor of Differentiation 1 (Id1) in Cancer and Cancer Therapy

“…Id1 is relevant to HCC dedifferentiation [88], Id1 levels are not only high in HCC cells, but also upregulated in HCV-infected hepatic cells or viral core gene-transfected cells, whereas they are very low in normal liver tissues [89]. Moreover, overexpressed Id1 is associated with patients' prognosis and HBx expression in hepatitis B virus-related HCC.…”

Oncogenicity of viral hepatitis B and C in the initiation of hepatic cancer stem cells

“…A previous study showed that CSC generation by HCV core protein was dependent on the endoglin (CD105), a TGF-β receptor complex. Besides the increase of CSC proteins antiapoptosis and proliferation are enhanced during infection or ectopic expression of HCV core [44] .…”