Primary HCC is the fifth most common cancer in the world and the third most common cause of cancer mortality. The major etiological factors leading to HCC are the infection of hepatitis B and C viruses (HBV and HCV), as well as consumption of aflatoxin B1 contaminated foods. Since a gender bias exists in the HCC incidence and cancer regression the objective of this proposal is to investigate the role of the androgen receptor (AR) in the development and growth of hepatocellular carcinoma (HCC) and explore the feasibility of targeting AR for treatment of HCC. Initially, the role of AR in HCC development and growth will be studied by comparing the carcinogen, N, N-diethylnitrosamine-induced HCC development and growth in wild type, general AR knockout (G-ARKO), and liver-specific AR knockout (L-ARKO) mice through determination of liver tumor incidence, rates of change in tumor foci number and size, and histochemical comparison of growth of preneoplastic foci, tumor cell proliferation and apoptosis indexes. These studies will be extended to HBV-mediated HCC development and growth through generation of G-ARKO and L- ARKO models of mice carrying HBV genome (HBV transgenic mice). The roles of AR in modulation of liver tumor growth deduced by ablation of AR in these mice models will be further confirmed by studying the effect of downregulating the expression of AR by AR-specific small interference RNA (AR-siRNA) on the growth of primary tumor cells of wild type and HBV transgenic mice in primary cultures and tumor xenografts in nude mice. The effect of AR-siRNA will be extended to the study of AR-expressing human hepatoma cells, both HBV-positive and HBV-negative, in tissue cultures and tumor xenografts. After having established that AR modulates the development and/or growth of liver tumor cells in these studies, the molecular mechanisms of how AR influences liver cancer incidence and progression will be studied via 4 different pathways. Public Relevance Statement: The success of this application will provide useful information pertaining to not only the role of AR in HCC development and growth, but also to the applicability of targeting AR for treatment of human primary HCC and eventually lead to more effective treatment regimens for this deadly neoplastic disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA122295-01A2
Application #
7323598
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2007-07-01
Project End
2012-05-31
Budget Start
2007-07-01
Budget End
2008-05-31
Support Year
1
Fiscal Year
2007
Total Cost
$292,600
Indirect Cost
Name
University of Rochester
Department
Pathology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Shyr, Chih-Rong; Tsai, Meng-Yin; Yeh, Shuyuan et al. (2010) Tumor suppressor PAX6 functions as androgen receptor co-repressor to inhibit prostate cancer growth. Prostate 70:190-9
Wu, Ming-Heng; Ma, Wen-Lung; Hsu, Cheng-Lung et al. (2010) Androgen receptor promotes hepatitis B virus-induced hepatocarcinogenesis through modulation of hepatitis B virus RNA transcription. Sci Transl Med 2:32ra35
Ma, Wen-Lung; Ma, Cheng-Lung; Hsu, Cheng-Lung et al. (2008) Androgen receptor is a new potential therapeutic target for the treatment of hepatocellular carcinoma. Gastroenterology 135:947-55, 955.e1-5
Niu, Yuanjie; Yeh, Shuyuan; Miyamoto, Hiroshi et al. (2008) Tissue prostate-specific antigen facilitates refractory prostate tumor progression via enhancing ARA70-regulated androgen receptor transactivation. Cancer Res 68:7110-9