Androgen receptor is a new potential therapeutic target for the treatment of hepatocellular carcinoma.
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.
Ma
Wen-Lung
WL
Department of Pathology, George Whipple Laboratory for Cancer Research, Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USA.
Ma
Cheng-Lung
CL
Hsu
Cheng-Lung
CL
Wu
Ming-Heng
MH
Wu
Chun-Te
CT
Wu
Cheng-Chia
CC
Lai
Jiann-Jyh
JJ
Jou
Yuh-Shan
YS
Chen
Chun-Wei
CW
Yeh
Shuyuan
S
Chang
Chawnshang
C
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
D059002:Androgen Receptor Antagonists; D003474:Curcumin; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011944:Receptors, Androgen; D013739:Testosterone; C471106:ASC-J9 compound