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Androgen receptor is a new potential therapeutic target for the treatment of hepatocellular carcinoma.
- Source :
-
Gastroenterology [Gastroenterology] 2008 Sep; Vol. 135 (3), pp. 947-55, 955.e1-5. Date of Electronic Publication: 2008 May 22. - Publication Year :
- 2008
-
Abstract
- Background & Aims: 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.<br />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.<br />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.<br />Conclusions: Our data point to AR, but not androgens, as a potential new and better therapeutic target for the battle of HCC.
- Subjects :
- Androgen Receptor Antagonists
Animals
Apoptosis
Carcinoma, Hepatocellular drug therapy
Carcinoma, Hepatocellular pathology
Cell Proliferation
Curcumin analogs & derivatives
Curcumin therapeutic use
DNA Damage
DNA Repair
Female
Genes, p53
Humans
Liver metabolism
Liver Neoplasms drug therapy
Liver Neoplasms pathology
Liver Neoplasms, Experimental metabolism
Liver Neoplasms, Experimental pathology
Male
Mice
Mice, Knockout
Mice, Nude
Oxidative Stress
RNA, Small Interfering therapeutic use
Reactive Oxygen Species metabolism
Testosterone blood
Carcinoma, Hepatocellular metabolism
Liver Neoplasms metabolism
Receptors, Androgen metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0012
- Volume :
- 135
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 18639551
- Full Text :
- https://doi.org/10.1053/j.gastro.2008.05.046