Androgen Receptor Is a New Potential Therapeutic Target for the Treatment of Hepatocellular Carcinoma

Cheng Lung Ma, Cheng Lung Hsu, Ming Heng Wu, Chun Te Wu, Cheng Chia Wu, Jiann Jyh Lai, Yuh Shan Jou, Chun Wei Chen, Shuyuan Yeh, Chawnshang Chang

研究成果: 雜誌貢獻文章同行評審

185 引文 斯高帕斯(Scopus)

摘要

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. 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 5α-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.
原文英語
期刊Gastroenterology
135
發行號3
DOIs
出版狀態已發佈 - 9月 2008
對外發佈

ASJC Scopus subject areas

  • 消化內科

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