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Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinoma.

Abstract

Hedgehog (Hh) pathway activation promotes many processes that occur during fibrogenic liver repair. Whether the Hh pathway modulates the outcomes of virally mediated liver injury has never been examined. Gene-profiling studies of human hepatocellular carcinomas (HCCs) demonstrate Hh pathway activation in HCCs related to chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Because most HCCs develop in cirrhotic livers, we hypothesized that Hh pathway activation occurs during fibrogenic repair of liver damage due to chronic viral hepatitis, and that Hh-responsive cells mediate disease progression and hepatocarciongenesis in chronic viral hepatitis. Immunohistochemistry and qRT-PCR analysis were used to analyze Hh pathway activation and identify Hh-responsive cell types in liver biopsies from 45 patients with chronic HBV or HCV. Hh signaling was then manipulated in cultured liver cells to directly assess the impact of Hh activity in relevant cell types. We found increased hepatic expression of Hh ligands in all patients with chronic viral hepatitis, and demonstrated that infection with HCV stimulated cultured hepatocytes to produce Hh ligands. The major cell populations that expanded during cirrhosis and HCC (ie, liver myofibroblasts, activated endothelial cells, and progenitors expressing markers of tumor stem/initiating cells) were Hh responsive, and higher levels of Hh pathway activity associated with cirrhosis and HCC. Inhibiting pathway activity in Hh-responsive target cells reduced fibrogenesis, angiogenesis, and growth. In conclusion, HBV/HCV infection increases hepatocyte production of Hh ligands and expands the types of Hh-responsive cells that promote liver fibrosis and cancer.

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  • Authors+Show Affiliations

    ,

    Division of Gastroenterology, Duke University, Durham, NC 27710, USA.

    , , , , , , , , , , , , , ,

    Source

    MeSH

    Adult
    Aged
    Carcinoma, Hepatocellular
    Cell Line, Tumor
    Cells, Cultured
    Disease Progression
    Female
    Hedgehog Proteins
    Hepatitis C, Chronic
    Hepatitis Viruses
    Hepatocytes
    Humans
    Liver
    Liver Cirrhosis
    Liver Neoplasms
    Male
    Middle Aged
    Signal Transduction
    Viral Proteins

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    20697376

    Citation

    Pereira, Thiago de Almeida, et al. "Viral Factors Induce Hedgehog Pathway Activation in Humans With Viral Hepatitis, Cirrhosis, and Hepatocellular Carcinoma." Laboratory Investigation; a Journal of Technical Methods and Pathology, vol. 90, no. 12, 2010, pp. 1690-703.
    Pereira Tde A, Witek RP, Syn WK, et al. Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinoma. Lab Invest. 2010;90(12):1690-703.
    Pereira, T. d. e. . A., Witek, R. P., Syn, W. K., Choi, S. S., Bradrick, S., Karaca, G. F., ... Diehl, A. M. (2010). Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinoma. Laboratory Investigation; a Journal of Technical Methods and Pathology, 90(12), pp. 1690-703. doi:10.1038/labinvest.2010.147.
    Pereira Tde A, et al. Viral Factors Induce Hedgehog Pathway Activation in Humans With Viral Hepatitis, Cirrhosis, and Hepatocellular Carcinoma. Lab Invest. 2010;90(12):1690-703. PubMed PMID: 20697376.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinoma. AU - Pereira,Thiago de Almeida, AU - Witek,Rafal P, AU - Syn,Wing-Kin, AU - Choi,Steve S, AU - Bradrick,Shelton, AU - Karaca,Gamze F, AU - Agboola,Kolade M, AU - Jung,Youngmi, AU - Omenetti,Alessia, AU - Moylan,Cynthia A, AU - Yang,Liu, AU - Fernandez-Zapico,Martin E, AU - Jhaveri,Ravi, AU - Shah,Vijay H, AU - Pereira,Fausto E, AU - Diehl,Anna M, Y1 - 2010/08/09/ PY - 2010/8/11/entrez PY - 2010/8/11/pubmed PY - 2011/1/5/medline SP - 1690 EP - 703 JF - Laboratory investigation; a journal of technical methods and pathology JO - Lab. Invest. VL - 90 IS - 12 N2 - Hedgehog (Hh) pathway activation promotes many processes that occur during fibrogenic liver repair. Whether the Hh pathway modulates the outcomes of virally mediated liver injury has never been examined. Gene-profiling studies of human hepatocellular carcinomas (HCCs) demonstrate Hh pathway activation in HCCs related to chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Because most HCCs develop in cirrhotic livers, we hypothesized that Hh pathway activation occurs during fibrogenic repair of liver damage due to chronic viral hepatitis, and that Hh-responsive cells mediate disease progression and hepatocarciongenesis in chronic viral hepatitis. Immunohistochemistry and qRT-PCR analysis were used to analyze Hh pathway activation and identify Hh-responsive cell types in liver biopsies from 45 patients with chronic HBV or HCV. Hh signaling was then manipulated in cultured liver cells to directly assess the impact of Hh activity in relevant cell types. We found increased hepatic expression of Hh ligands in all patients with chronic viral hepatitis, and demonstrated that infection with HCV stimulated cultured hepatocytes to produce Hh ligands. The major cell populations that expanded during cirrhosis and HCC (ie, liver myofibroblasts, activated endothelial cells, and progenitors expressing markers of tumor stem/initiating cells) were Hh responsive, and higher levels of Hh pathway activity associated with cirrhosis and HCC. Inhibiting pathway activity in Hh-responsive target cells reduced fibrogenesis, angiogenesis, and growth. In conclusion, HBV/HCV infection increases hepatocyte production of Hh ligands and expands the types of Hh-responsive cells that promote liver fibrosis and cancer. SN - 1530-0307 UR - https://www.unboundmedicine.com/medline/citation/20697376/Viral_factors_induce_Hedgehog_pathway_activation_in_humans_with_viral_hepatitis_cirrhosis_and_hepatocellular_carcinoma_ L2 - http://dx.doi.org/10.1038/labinvest.2010.147 DB - PRIME DP - Unbound Medicine ER -