Androgen Receptor Roles in Liver Cancer Incidence and Progression

描述(申请人提供)：原发性肝癌是世界上第五种最常见的癌症，也是导致癌症死亡的第三大常见原因。肝细胞癌的主要病因是乙型和丙型肝炎病毒(乙肝病毒和丙型肝炎病毒)的感染，以及食用黄曲霉毒素B1污染的食物。鉴于肝细胞癌的发病和消退存在性别差异，本研究旨在探讨雄激素受体在肝细胞癌发生、发展中的作用，并探讨雄激素受体靶向治疗肝细胞癌的可行性。首先，将通过比较致癌物、N，N-二乙基亚硝胺诱导的野生型、普通AR基因敲除(G-ARKO)和肝脏特异性AR基因敲除(L-ARKO)小鼠的肝癌发生和生长，通过测定肝脏肿瘤发生率、肿瘤灶数目和大小的变化率，以及癌前病变灶生长、肿瘤细胞增殖和凋亡指标的组织化学比较，来研究AR在肝癌发生和生长中的作用。这些研究将通过建立携带乙肝病毒基因组的G-Arko和L-Arko小鼠模型(乙肝转基因小鼠)，扩展到乙肝病毒介导的肝癌的发展和生长。通过研究AR特异性小干扰RNA(AR-siRNA)下调AR表达对野生型原代肿瘤细胞、原代培养的HBV转基因小鼠和裸鼠移植瘤生长的影响，进一步证实AR在去除AR诱导的小鼠肝肿瘤生长中的作用。AR-siRNA的作用将扩展到组织培养和肿瘤移植瘤中表达AR的人肝癌细胞，包括HBV阳性和HBV阴性的细胞。在这些研究中确定AR调控肝癌细胞的发育和/或生长后，将通过4种不同的途径来研究AR影响肝癌发生和发展的分子机制。公开相关声明：这一应用的成功不仅将提供有关AR在肝癌的发展和生长中的作用的有用信息，还将提供有关将AR作为靶向治疗人类原发性肝癌的适用性的有用信息，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.