Androgen receptor promotes hepatitis B virus-induced hepatocarcinogenesis through modulation of hepatitis B virus RNA transcription

Ming Heng Wu, Wen Lung Ma, Cheng Lung Hsu, Yuh Ling Chen, Jing Hsiung James Ou, Charlotte Kathryn Ryan, Yao Ching Hung, Shuyuan Yeh, Chawnshang Chang

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Abstract

Hepatitis B virus (HBV)-induced hepatitis and carcinogen-induced hepatocellular carcinoma (HCC) are associated with serum androgen concentration. However, how androgen or the androgen receptor (AR) contributes to HBV-induced hepatocarcinogenesis remains unclear. We found that hepatic AR promotes HBV-induced hepatocarcinogenesis in HBV transgenic mice that lack AR only in the liver hepatocytes (HBV-L-AR-/y). HBV-L-AR-/y mice that received a low dose of the carcinogen N′-N′-diethylnitrosamine (DEN) have a lower incidence of HCC and present with smaller tumor sizes, fewer foci formations, and less α-fetoprotein HCC marker than do their wild-type HBV-AR+/y littermates. We found that hepatic AR increases the HBV viral titer by enhancing HBV RNA transcription through direct binding to the androgen response element near the viral core promoter. This activity forms a positive feedback mechanism with cooperation with its downstream target gene HBx protein to promote hepatocarcinogenesis. Administration of a chemical compound that selectively degrades AR, ASC-J9, was able to suppress HCC tumor size in DEN-HBV-AR+/y mice. These results demonstrate that targeting the AR, rather than the androgen, could be developed as a new therapy to battle HBV-induced HCC.

Original languageEnglish
JournalScience Translational Medicine
Volume2
Issue number32
DOIs
Publication statusPublished - 2010
Externally publishedYes

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Androgen Receptors
Hepatitis B virus
RNA
Hepatocellular Carcinoma
Androgens
Virus Receptors
Diethylnitrosamine
Carcinogens
Liver
Fetal Proteins
Response Elements
Viral Load
Transgenic Mice
Hepatitis
Hepatocytes
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

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Androgen receptor promotes hepatitis B virus-induced hepatocarcinogenesis through modulation of hepatitis B virus RNA transcription. / Wu, Ming Heng; Ma, Wen Lung; Hsu, Cheng Lung; Chen, Yuh Ling; Ou, Jing Hsiung James; Ryan, Charlotte Kathryn; Hung, Yao Ching; Yeh, Shuyuan; Chang, Chawnshang.

In: Science Translational Medicine, Vol. 2, No. 32, 2010.

Research output: Contribution to journalArticle

Wu, Ming Heng ; Ma, Wen Lung ; Hsu, Cheng Lung ; Chen, Yuh Ling ; Ou, Jing Hsiung James ; Ryan, Charlotte Kathryn ; Hung, Yao Ching ; Yeh, Shuyuan ; Chang, Chawnshang. / Androgen receptor promotes hepatitis B virus-induced hepatocarcinogenesis through modulation of hepatitis B virus RNA transcription. In: Science Translational Medicine. 2010 ; Vol. 2, No. 32.
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