Background & Aims Early reports suggested androgen/androgen receptor (AR) signals promote hepatocarcinogenesis. However, all antiandrogen clinical trials failed in advanced hepatocellular carcinoma (HCC) without reasonable explanations. We have examined AR functions in HCC cancer metastasis in this study. Methods We examined hepatic AR roles in HCC metastasis by comparing liver hepatocyte AR knockout and wildtype in carcinogen-induced HCC mouse model. We examined tumor histology, cancer metastatic risks, and cancer survival in vivo, as well as cell anoikis and migration using primary hepatic tumor culture in vitro. We also examined therapeutic potentials of AR expression combined with molecular targeting agent, Sorafenib, in HCC metastasis mouse model. Results We found a novel cancer phenotype in which mice lacking hepatic AR developed more undifferentiated tumors and larger tumor size at later metastatic stage. These mice also died earlier with increased lung metastasis, suggesting hepatic-AR may play dual yet opposite roles to promote HCC initiation but suppress HCC metastasis. Mechanistic dissection found that hepatic AR could enhance anoikis and suppress migration of HCC cells via suppression of p38 phosphorylation/activation and the NFκB-MMP9 pathway, respectively. In addition, the in vivo pre-clinical trials concluded that a combination therapy of increased AR expression and reduced multiple-kinase inhibitor (Sorafenib) exhibited better therapeutic efficacy. Conclusions Our study demonstrated that AR could orchestrate intrahepatic signalling hierarchies and cellular behavior, consequently affect HCC progression. Results from combination therapy shed a light on developing new therapeutic paradigm for battling HCC at later metastatic stage.

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.