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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 in vitro 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.IMPORTANCE 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.

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  • Authors+Show Affiliations

    ,

    Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA.

    ,

    Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA.

    ,

    Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA.

    Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA rayr@slu.edu. Department of Molecular Microbiology & Immunology, Saint Louis University, St. Louis, Missouri, USA.

    Source

    Journal of virology 91:21 2017 11 01 pg

    MeSH

    Activin Receptors, Type II
    Carcinoma, Hepatocellular
    Cell Proliferation
    Cells, Cultured
    Endoglin
    Hepacivirus
    Hepatocytes
    Humans
    Liver Neoplasms
    Signal Transduction
    Viral Core Proteins

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    28794048

    Citation

    Kwon, Young-Chan, et al. "Hepatitis C Virus Core Protein Modulates Endoglin (CD105) Signaling Pathway for Liver Pathogenesis." Journal of Virology, vol. 91, no. 21, 2017.
    Kwon YC, Sasaki R, Meyer K, et al. Hepatitis C Virus Core Protein Modulates Endoglin (CD105) Signaling Pathway for Liver Pathogenesis. J Virol. 2017;91(21).
    Kwon, Y. C., Sasaki, R., Meyer, K., & Ray, R. (2017). Hepatitis C Virus Core Protein Modulates Endoglin (CD105) Signaling Pathway for Liver Pathogenesis. Journal of Virology, 91(21), doi:10.1128/JVI.01235-17.
    Kwon YC, et al. Hepatitis C Virus Core Protein Modulates Endoglin (CD105) Signaling Pathway for Liver Pathogenesis. J Virol. 2017 11 1;91(21) PubMed PMID: 28794048.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Hepatitis C Virus Core Protein Modulates Endoglin (CD105) Signaling Pathway for Liver Pathogenesis. AU - Kwon,Young-Chan, AU - Sasaki,Reina, AU - Meyer,Keith, AU - Ray,Ranjit, Y1 - 2017/10/13/ PY - 2017/07/18/received PY - 2017/08/06/accepted PY - 2017/8/11/pubmed PY - 2017/12/15/medline PY - 2017/8/11/entrez KW - HCC KW - HCV KW - angiogenesis KW - core KW - endoglin KW - hepatitis C virus JF - Journal of virology JO - J. Virol. VL - 91 IS - 21 N2 - 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 in vitro 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.IMPORTANCE 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. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/28794048/Hepatitis_C_Virus_Core_Protein_Modulates_Endoglin__CD105__Signaling_Pathway_for_Liver_Pathogenesis_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/28794048/ DB - PRIME DP - Unbound Medicine ER -