Androgen receptor promotes hepatitis B virus-induced hepatocarcinogenesis through modulation of hepatitis B virus RNA transcription.
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 alpha-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.
Wu
Ming-Heng
MH
Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan.
Ma
Wen-Lung
WL
Hsu
Cheng-Lung
CL
Chen
Yuh-Ling
YL
Ou
Jing-Hsiung James
JH
Ryan
Charlotte Kathryn
CK
Hung
Yao-Ching
YC
Yeh
Shuyuan
S
Chang
Chawnshang
C
D059002:Androgen Receptor Antagonists; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control / Q000821:virology*; D002472:Cell Transformation, Viral / Q000235:genetics; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology; D004052:Diethylnitrosamine; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000150:complications / Q000235:genetics*; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control / Q000821:virology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012367:RNA, Viral / Q000378:metabolism*; D011944:Receptors, Androgen / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D047368:Tumor Burden; D019562:Viral Load
D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D003474:Curcumin; D004052:Diethylnitrosamine; D012367:RNA, Viral; D011944:Receptors, Androgen; C471106:ASC-J9 compound