title: Sorafenib Action in Hepatitis B Virus X-Activated Oncogenic Androgen Pathway in Liver through SHP-1.
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.
authors.affiliation: 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.
authors.forename: Sheng-Han
authors.initials: SH
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Shiou-Hwei
authors.initials: SH
authors.lastname: Yeh
authors.affiliation: 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.
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.affiliation: 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.
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Wei-Hsiang
authors.initials: WH
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Ting-Fen
authors.initials: TF
authors.lastname: Tsai
authors.affiliation: 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.
authors.forename: Yuan-Chi
authors.initials: YC
authors.lastname: Teng
authors.affiliation: 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.
authors.forename: Ding-Shinn
authors.initials: DS
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
mesh_terms: D000367:Age Factors; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000517:prevention & control* / Q000821:virology; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006509:Hepatitis B / Q000150:complications*; D006515:Hepatitis B virus / Q000378:metabolism* / Q000472:pathogenicity; D015994:Incidence; D008113:Liver Neoplasms / Q000517:prevention & control* / Q000821:virology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009919:Orchiectomy; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011944:Receptors, Androgen / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011944:Receptors, Androgen; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D009536:Niacinamide; D000077157:Sorafenib; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse