Sex Hormone Receptor May Explain Higher Risk of HCC

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Sex Hormone Receptor May Explain Higher Risk of Hepatocellular Carcinoma in Men

SUMMARY:  Interaction between hepatitis B virus (HBV) and the androgen receptor in the liver promotes viral replication and triggers cell changes that lead to development of hepatocellular carcinoma, according to a study in mice described in the May 19, 2010 issue of Science Translational Medicine. Since men have more active androgen receptors than women, these findings help explain why men with hepatitis B are more prone to liver cancer, and suggest that blocking androgen receptors in the liver might be an effective treatment.

               
                               

By Liz Highleyman

Left: liver cancer without androgen receptor; Right: liver cancer with androgen receptor (Source: University of Rochester)

Over years or decades, chronic HBV infection can lead to serious liver disease including cirrhosis and hepatocellular carcinoma (HCC), a form of primary liver cancer. Many factors, including sex, influence the risk of developing HCC, but the underlying biological mechanisms are not fully understood. Men account for about 75% of all liver cancer cases.

Androgens are considered male hormones -- although women also produce them in smaller amounts -- and they are responsible for male secondary sex characteristics; androgen receptors, which must interact with androgens in order for them to exert their effects, are more active in men. Prior research has shown that liver damage due to hepatitis B is associated with androgen levels in the blood, but the reason for this link is unclear.

Ming-Heng Wu and colleagues from Taiwan and the U.S. performed a study of mice to learn more about the association between androgens and liver cancer. They used transgenic or genetically altered HBV-L-AR(-/y) mice with hepatitis B that lacked androgen receptors only in hepatocytes, or working liver cells (blocking androgen receptors throughout the body would have the effect of chemical castration).

Results
        Hepatic androgen receptors promoted HBV-induced development of HCC.
        After 6 months, more than 90% of mice with normal androgen receptors developed HCC, compared with just 27% of those with missing androgen receptors.
        HBV-L-AR(-/y) mice without androgen receptors that received a low dose of the carcinogen N'-N'-diethylnitrosamine had a lower likelihood of developing HCC than wild-type (non-mutated) littermates.
        Altered mice that did develop cancer had smaller tumor sizes, fewer foci formations, and lower alpha-fetoprotein levels than wild-type mice.
        The androgen receptor bound to the androgen response element in HBV DNA, near the virus core promoter, thereby enhancing transcription of HBV genetic material and leading to increased viral load.
        This triggered a positive feedback mechanism leading to expression of the gene that produces the HBx protein and others known to have an oncogenic or cancer-causing effect.
        Administration of a chemical (ASC-J9) that selectively degrades androgen receptors reduced HCC tumor size.

These results, the study authors concluded, "demonstrate that targeting the androgen receptor, rather than the androgen, could be developed as a new therapy to battle HBV-induced HCC."

"Our study is the first in vivo evidence to demonstrate a direct connection between HBV-induced liver cancer and the androgen receptor," co-author Chawnshang Chang said in a press release issued by the University of Rochester. "This is important because so far most work has focused on eliminating total serum androgen levels, a type of therapy that has shown little success."

Chang previously found that the androgen receptor is likewise associated with development of prostate cancer and bladder cancer (which also occurs much more often in men than women). He also developed ASC-J9, a synthetic compound based on compounds found in curcumin.

Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan; George Whipple Lab for Cancer Research, Departments of Pathology and Urology and Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY; Sex Hormone Research Center, Graduate Institute of Clinical Medical Science, Department of Obstetrics and Gynecology, China Medical University/Hospital, Taichung, Taiwan; Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung University/Memorial Hospital, Taoyuan, Taiwan; Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA.

6/8/10

Reference

MH Wu, WL Ma, CL Hsu, and others. Androgen receptor promotes hepatitis B virus-induced hepatocarcinogenesis through modulation of hepatitis B virus RNA transcription. Science Translational Medicine 2(32): 32ra35 (Abstract). May 19, 2010

Other source
University of Rochester. Androgen Receptor May Explain Male Dominance in Liver Cancer. Press release. May 19, 2010.



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