Androgen Receptor Promotes Hepatitis B Virus–Induced Hepatocarcinogenesis Through Modulation of Hepatitis B Virus RNA Transcription

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.

Androgen receptor in hepatocarcinogenesis: Recent developments and perspectives

“…Another study, which stably transfected functional AR into AR-negative HCC cells, revealed that cell growth was increased in the absence of androgen (46). These observations indicate that non-androgen-mediated AR signals may also be involved in hepatocarcinogenesis.…”

“…This observation confirms the importance of androgen and AR in the mediation of HBV replication. A study by Wu et al (46) indicated that an aberrant overexpression of AR in HCC cells cooperates with HBV to enhance cell growth and invasion in vitro, and initiate HCC in vivo. Further studies have demonstrated that HBx, a HBV-encoded protein required for efficient viral replication, enhanced the gene transactivation activity of AR in the presence of androgens (38,39).…”

Androgen Receptor and Hepatocellular Carcinoma

“…HBx enhances the AR transcriptional activity through two kinases: c-Src and glycogen synthase kinase-3beta kinase [51]. AR promotes HBV-induced hepatocarcinogenesis through modulation of HBV RNA transcription [52]. The androgen pathway can increase the transcription of HBV through direct binding to the ARE sites in HBV enhancer I, leading to a higher HBV titer in male carriers and increased risk of HCC [53].…”

A potential explanation of the reported low prevalence of hepatitis B virus infection in patients with systemic lupus erythematosus

“…Incidental Wndings in each were that healthy volunteer HBV carriers had higher testosterone (T) concentrations than healthy uninfected volunteer controls (P = 0.045 and P = 0.0006, respectively, both two-way). The reason for this is not established and not directly relevant to the present note (though it may relate to variation in rates of viral replication in diVerent hormonal environments, if we may be guided by mouse models [4][5][6]). …”