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Sorafenib Action in Hepatitis B Virus X-Activated Oncogenic Androgen Pathway in Liver through SHP-1.
- Source :
-
Journal of the National Cancer Institute [J Natl Cancer Inst] 2015 Jul 23; Vol. 107 (10). Date of Electronic Publication: 2015 Jul 23 (Print Publication: 2015). - Publication Year :
- 2015
-
Abstract
- Background: Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) shows a higher incidence in men, mainly because of hepatitis B X (HBx)-mediated enhancement of androgen receptor (AR) activity. We aimed to examine this pathway in hepatocarcinogenesis and to identify drug(s) specifically blocking this carcinogenic event in the liver.<br />Methods: HBx transgenic mice that spontaneously develop HCC (n = 28-34 per group) were used, either by knockout of hepatic AR or by castration. Efficacy of several HCC-targeted drugs in suppressing HBx-induced AR activity was evaluated, and cellular factors mediating suppression were investigated in cultured cells. Tissue specificity of the candidate drug was validated using mouse tissues. Data were analyzed with Chi-square and Student's t tests. All statistical tests were two-sided.<br />Results: The androgen pathway was shown to be important in early stage hepatocarcinogenesis of HBx transgenic mice. The tumor incidence was decreased from 80% to 32% by AR knockout (P < .001) and from 90% to 25% by early castration (P < .001). Sorafenib markedly inhibited the HBx-enhanced AR activity through activating the SHP-1 phosphatase, which antagonized the activation of Akt/GSK3β and c-Src by HBx. Moreover, SHP-1 protein level was much higher in the liver than in testis, which enabled sorafenib to inhibit aberrant AR activity in the HBx-expressing liver, while not affecting the physiological AR function in normal liver or testis.<br />Conclusions: The androgen pathway may be a druggable target for the chemoprevention of HBV-related HCC, and sorafenib might be used as a tissue- and disease-specific regimen for the chemoprevention of HBV-related HCC.<br /> (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Subjects :
- Age Factors
Animals
Carcinoma, Hepatocellular virology
Enzyme Activation drug effects
Gene Expression Regulation, Neoplastic drug effects
Glycogen Synthase Kinase 3 antagonists & inhibitors
Glycogen Synthase Kinase 3 beta
Hepatitis B virus pathogenicity
Incidence
Liver Neoplasms virology
Male
Mice
Mice, Transgenic
Niacinamide pharmacology
Orchiectomy
Protein Tyrosine Phosphatase, Non-Receptor Type 6 drug effects
Proto-Oncogene Proteins c-akt antagonists & inhibitors
Receptors, Androgen metabolism
Signal Transduction drug effects
Sorafenib
Trans-Activators genetics
Viral Regulatory and Accessory Proteins
Antineoplastic Agents pharmacology
Carcinoma, Hepatocellular prevention & control
Hepatitis B complications
Hepatitis B virus metabolism
Liver Neoplasms prevention & control
Niacinamide analogs & derivatives
Phenylurea Compounds pharmacology
Protein Kinase Inhibitors pharmacology
Protein Tyrosine Phosphatase, Non-Receptor Type 6 metabolism
Receptors, Androgen drug effects
Trans-Activators metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2105
- Volume :
- 107
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of the National Cancer Institute
- Publication Type :
- Academic Journal
- Accession number :
- 26206949
- Full Text :
- https://doi.org/10.1093/jnci/djv190