title: Androgen receptor is a new potential therapeutic target for the treatment of hepatocellular carcinoma.
abstract: OBJECTIVE
  Androgen effects on hepatocellular carcinoma (HCC) remain controversial and androgen ablation therapy to treat HCC also leads to inconsistent results. Here we examine androgen receptor (AR) roles in hepatocarcinogenesis using mice lacking AR in hepatocytes.
  
  
  METHODS
  By using the Cre-Lox conditional knockout mice model injected with carcinogen, we examined the AR roles in hepatocarcinogenesis. We also tested the possible roles of AR in cellular oxidative stress and DNA damage sensing/repairing systems. By using AR degrading compound, ASC-J9, or AR-small interference RNA, we also examined the therapeutic potentials of targeting AR in HCC.
  
  
  RESULTS
  We found AR expression was increased in human HCC compared with normal livers. We also found mice lacking hepatic AR developed later and less HCC than their wild-type littermates with comparable serum testosterone in both male and female mice. Addition of functional AR in human HCC cells also resulted in the promotion of cell growth in the absence or presence of 5alpha-dihydrotestosterone. Mechanistic dissection suggests that AR may promote hepatocarcinogenesis via increased cellular oxidative stress and DNA damage, as well as suppression of p53-mediated DNA damage sensing/repairing system and cell apoptosis. Targeting AR directly via either AR-small interference RNA or ASC-J9 resulted in suppression of HCC in both ex vivo cell lines and in vivo mice models.
  
  
  CONCLUSIONS
  Our data point to AR, but not androgens, as a potential new and better therapeutic target for the battle of HCC.
authors.affiliation: Department of Pathology, George Whipple Laboratory for Cancer Research, Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Wen-Lung
authors.initials: WL
authors.lastname: Ma
authors.forename: Cheng-Lung
authors.initials: CL
authors.lastname: Ma
authors.forename: Cheng-Lung
authors.initials: CL
authors.lastname: Hsu
authors.forename: Ming-Heng
authors.initials: MH
authors.lastname: Wu
authors.forename: Chun-Te
authors.initials: CT
authors.lastname: Wu
authors.forename: Cheng-Chia
authors.initials: CC
authors.lastname: Wu
authors.forename: Jiann-Jyh
authors.initials: JJ
authors.lastname: Lai
authors.forename: Yuh-Shan
authors.initials: YS
authors.lastname: Jou
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Chen
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Yeh
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D059002:Androgen Receptor Antagonists; D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D003474:Curcumin / Q000031:analogs & derivatives / Q000627:therapeutic use; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D016158:Genes, p53; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D013739:Testosterone / Q000097:blood
chemical_list: D059002:Androgen Receptor Antagonists; D003474:Curcumin; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011944:Receptors, Androgen; D013739:Testosterone; C471106:ASC-J9 compound