Sheng-Han Wang1, Shiou-Hwei Yeh2, Chung-Wai Shiau1, Kuen-Feng Chen1, Wei-Hsiang Lin1, Ting-Fen Tsai1, Yuan-Chi Teng1, Ding-Shinn Chen1, Pei-Jer Chen1. 1. Department of Microbiology (SHW, SHY, WHL, PJC), NTU Center for Genomic Medicine (SHY, DSC, PJC), and Graduate Institute of Clinical Medicine (DSC, PJC), National Taiwan University College of Medicine, Taipei, Taiwan; Department of Laboratory Medicine (SHY), Department of Medical Research (KFC), and National Center of Excellence for Clinical Trial and Research (KFC), National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan (DSC, PJC); Institute of Biopharmaceutical Sciences (CWS) and Department of Life Sciences and Institute of Genome Sciences (TFT, YCT), National Yang-Ming University, Taipei, Taiwan. 2. Department of Microbiology (SHW, SHY, WHL, PJC), NTU Center for Genomic Medicine (SHY, DSC, PJC), and Graduate Institute of Clinical Medicine (DSC, PJC), National Taiwan University College of Medicine, Taipei, Taiwan; Department of Laboratory Medicine (SHY), Department of Medical Research (KFC), and National Center of Excellence for Clinical Trial and Research (KFC), National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan (DSC, PJC); Institute of Biopharmaceutical Sciences (CWS) and Department of Life Sciences and Institute of Genome Sciences (TFT, YCT), National Yang-Ming University, Taipei, Taiwan. shyeh@ntu.edu.tw.
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. 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. 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. 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.
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. METHODS:HBxtransgenic 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. RESULTS: The androgen pathway was shown to be important in early stage hepatocarcinogenesis of HBxtransgenic 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. 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.
Authors: Anees M Dauki; James S Blachly; Esko A Kautto; Sameera Ezzat; Mohamed H Abdel-Rahman; Christopher C Coss Journal: Cancer Res Date: 2019-11-04 Impact factor: 12.701
Authors: James J Harding; Robin K Kelley; Benjamin Tan; Marinela Capanu; Gian Kinh Do; Jinru Shia; Joanne F Chou; Christine S Ferrer; Chayma Boussayoud; Kerri Muenkel; Hooman Yarmohammadi; Imane El Dika; Danny N Khalil; Carmen Ruiz; Mariam Rodriguez-Lee; Peter Kuhn; John Wilton; Renuka Iyer; Ghassan K Abou-Alfa Journal: Oncologist Date: 2020-07-02