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Hedgehog signaling blockade delays hepatocarcinogenesis induced by hepatitis B virus X protein.

Abstract

The hepatitis B virus (HBV) encoded X protein (HBx) contributes centrally to the pathogenesis of hepatocellular carcinoma (HCC). Aberrant activation of the Hedgehog (Hh) pathway has been linked to many tumor types including HCC. Thus, experiments were designed to test the hypothesis that HBx promotes HCC via activation of Hh signaling. HBx expression correlated with an upregulation of Hh markers in human liver cancer cell lines, in liver samples from HBV infected patients with HCC, and in the livers of HBx transgenic mice (HBxTg) that develop hepatitis, steatosis, and dysplasia, culminating in the appearance of HCC. The findings in human samples provide clinical validation for the in vitro results and those in the HBxTg. Blockade of Hh signaling inhibited HBx stimulation of cell migration, anchorage-independent growth, tumor development in HBxTg, and xenograft growth in nude mice. Results suggest that the ability of HBx to promote cancer is at least partially dependent upon the activation of the Hh pathway. This study provides biologic evidence for the role of Hh signaling in the pathogenesis of HBV-mediated HCC and suggests cause and effect for the first time. The observation that inhibition of Hh signaling partially blocked the ability of HBx to promote growth and migration in vitro and tumorigenesis in two animal models implies that Hh signaling may represent an "oncogene addiction" pathway for HBV-associated HCC. This work could be central to designing specific treatments that target early development and progression of HBx-mediated HCC.

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  • Authors+Show Affiliations

    ,

    Department of Biology, Temple University, Philadelphia, Pennsylvania 19122, USA. areg@temple.edu

    , , , , , ,

    Source

    Cancer research 72:22 2012 Nov 15 pg 5912-20

    MeSH

    Animals
    Carcinoma, Hepatocellular
    Cell Growth Processes
    Cell Movement
    Cell Transformation, Neoplastic
    Hedgehog Proteins
    Hep G2 Cells
    Humans
    Liver Neoplasms
    Male
    Mice
    Mice, Nude
    Mice, Transgenic
    Signal Transduction
    Trans-Activators
    Transfection

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    22986746

    Citation

    Arzumanyan, Alla, et al. "Hedgehog Signaling Blockade Delays Hepatocarcinogenesis Induced By Hepatitis B Virus X Protein." Cancer Research, vol. 72, no. 22, 2012, pp. 5912-20.
    Arzumanyan A, Sambandam V, Clayton MM, et al. Hedgehog signaling blockade delays hepatocarcinogenesis induced by hepatitis B virus X protein. Cancer Res. 2012;72(22):5912-20.
    Arzumanyan, A., Sambandam, V., Clayton, M. M., Choi, S. S., Xie, G., Diehl, A. M., ... Feitelson, M. A. (2012). Hedgehog signaling blockade delays hepatocarcinogenesis induced by hepatitis B virus X protein. Cancer Research, 72(22), pp. 5912-20. doi:10.1158/0008-5472.CAN-12-2329.
    Arzumanyan A, et al. Hedgehog Signaling Blockade Delays Hepatocarcinogenesis Induced By Hepatitis B Virus X Protein. Cancer Res. 2012 Nov 15;72(22):5912-20. PubMed PMID: 22986746.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Hedgehog signaling blockade delays hepatocarcinogenesis induced by hepatitis B virus X protein. AU - Arzumanyan,Alla, AU - Sambandam,Vaishnavi, AU - Clayton,Marcia M, AU - Choi,Steve S, AU - Xie,Guanhua, AU - Diehl,Anna Mae, AU - Yu,Dae-Yeul, AU - Feitelson,Mark A, Y1 - 2012/09/17/ PY - 2012/9/19/entrez PY - 2012/9/19/pubmed PY - 2013/3/6/medline SP - 5912 EP - 20 JF - Cancer research JO - Cancer Res. VL - 72 IS - 22 N2 - The hepatitis B virus (HBV) encoded X protein (HBx) contributes centrally to the pathogenesis of hepatocellular carcinoma (HCC). Aberrant activation of the Hedgehog (Hh) pathway has been linked to many tumor types including HCC. Thus, experiments were designed to test the hypothesis that HBx promotes HCC via activation of Hh signaling. HBx expression correlated with an upregulation of Hh markers in human liver cancer cell lines, in liver samples from HBV infected patients with HCC, and in the livers of HBx transgenic mice (HBxTg) that develop hepatitis, steatosis, and dysplasia, culminating in the appearance of HCC. The findings in human samples provide clinical validation for the in vitro results and those in the HBxTg. Blockade of Hh signaling inhibited HBx stimulation of cell migration, anchorage-independent growth, tumor development in HBxTg, and xenograft growth in nude mice. Results suggest that the ability of HBx to promote cancer is at least partially dependent upon the activation of the Hh pathway. This study provides biologic evidence for the role of Hh signaling in the pathogenesis of HBV-mediated HCC and suggests cause and effect for the first time. The observation that inhibition of Hh signaling partially blocked the ability of HBx to promote growth and migration in vitro and tumorigenesis in two animal models implies that Hh signaling may represent an "oncogene addiction" pathway for HBV-associated HCC. This work could be central to designing specific treatments that target early development and progression of HBx-mediated HCC. SN - 1538-7445 UR - https://www.unboundmedicine.com/medline/citation/22986746/Hedgehog_signaling_blockade_delays_hepatocarcinogenesis_induced_by_hepatitis_B_virus_X_protein_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=22986746 DB - PRIME DP - Unbound Medicine ER -