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

Publication ,  Journal Article
Arzumanyan, A; Sambandam, V; Clayton, MM; Choi, SS; Xie, G; Diehl, AM; Yu, D-Y; Feitelson, MA
Published in: Cancer Res
November 15, 2012

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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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

November 15, 2012

Volume

72

Issue

22

Start / End Page

5912 / 5920

Location

United States

Related Subject Headings

  • Viral Regulatory and Accessory Proteins
  • Transfection
  • Trans-Activators
  • Signal Transduction
  • Oncology & Carcinogenesis
  • Mice, Transgenic
  • Mice, Nude
  • Mice
  • Male
  • Liver Neoplasms
 

Citation

APA
Chicago
ICMJE
MLA
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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 Res, 72(22), 5912–5920. https://doi.org/10.1158/0008-5472.CAN-12-2329
Arzumanyan, Alla, Vaishnavi Sambandam, Marcia M. Clayton, Steve S. Choi, Guanhua Xie, Anna Mae Diehl, Dae-Yeul Yu, and Mark A. Feitelson. “Hedgehog signaling blockade delays hepatocarcinogenesis induced by hepatitis B virus X protein.Cancer Res 72, no. 22 (November 15, 2012): 5912–20. https://doi.org/10.1158/0008-5472.CAN-12-2329.
Arzumanyan A, Sambandam V, Clayton MM, Choi SS, Xie G, Diehl AM, et al. Hedgehog signaling blockade delays hepatocarcinogenesis induced by hepatitis B virus X protein. Cancer Res. 2012 Nov 15;72(22):5912–20.
Arzumanyan, Alla, et al. “Hedgehog signaling blockade delays hepatocarcinogenesis induced by hepatitis B virus X protein.Cancer Res, vol. 72, no. 22, Nov. 2012, pp. 5912–20. Pubmed, doi:10.1158/0008-5472.CAN-12-2329.
Arzumanyan A, Sambandam V, Clayton MM, Choi SS, Xie G, Diehl AM, Yu D-Y, Feitelson MA. Hedgehog signaling blockade delays hepatocarcinogenesis induced by hepatitis B virus X protein. Cancer Res. 2012 Nov 15;72(22):5912–5920.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

November 15, 2012

Volume

72

Issue

22

Start / End Page

5912 / 5920

Location

United States

Related Subject Headings

  • Viral Regulatory and Accessory Proteins
  • Transfection
  • Trans-Activators
  • Signal Transduction
  • Oncology & Carcinogenesis
  • Mice, Transgenic
  • Mice, Nude
  • Mice
  • Male
  • Liver Neoplasms