Androgen Receptor Roles in Liver Cancer Incidence and Progression

描述（由申请人提供）：原发性肝细胞癌是世界上第五大常见癌症，也是癌症死亡的第三大常见原因。导致肝细胞癌的主要病因是B和丙型肝炎病毒（HBV和HCV）的感染，以及食用黄曲霉毒素B1污染的食物。由于HCC发病率和癌症消退存在性别偏倚，因此本研究的目的是研究雄激素受体（AR）在肝细胞癌（HCC）发生和生长中的作用，并探索靶向AR治疗HCC的可行性。首先，通过测定肝肿瘤发生率、肿瘤病灶数量和大小的变化率以及癌前病灶生长的组织化学比较，比较致癌物、N，N-二乙基亚硝胺诱导的野生型、一般AR敲除（G-ARKO）和肝特异性AR敲除（L-ARKO）小鼠中HCC的发展和生长，研究AR在HCC发展和生长中的作用，肿瘤细胞增殖和凋亡指标。这些研究将通过产生携带HBV基因组的小鼠（HBV转基因小鼠）的G-ARKO和L-ARKO模型扩展到HBV介导的HCC发展和生长。通过研究AR特异性小干扰RNA（AR-siRNA）下调AR表达对野生型和HBV转基因小鼠原代培养的肿瘤细胞和裸鼠肿瘤移植瘤生长的影响，将进一步证实AR在这些小鼠模型中通过消融AR推断的肝肿瘤生长调节中的作用。AR-siRNA的作用将扩展到组织培养和肿瘤异种移植物中表达AR的人肝癌细胞（HBV阳性和HBV阴性）的研究。在这些研究中确定AR调节肝肿瘤细胞的发育和/或生长后，将通过4种不同的途径研究AR如何影响肝癌发病率和进展的分子机制。公共相关性声明：该应用的成功将提供有用的信息，不仅涉及AR在HCC发展和生长中的作用，而且还涉及靶向AR治疗人类原发性HCC的适用性，并最终导致这种致命肿瘤疾病的更有效的治疗方案。

DESCRIPTION (provided by applicant): 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.