Androgen Receptor Roles in Liver Cancer Incidence and Progression

雄激素受体在肝癌发病和进展中的作用

基本信息

批准号：
7835801
负责人：
CHAWNSHANG CHANG
金额：
$ 29.26万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7835801
关键词：
Ablation Affinity Aflatoxin B Aflatoxin B1 Alcohol consumption Androgen Antagonists Androgen Receptor Androgens Apoptosis Apoptotic Cancer Etiology Carcinogens Castration Cell Proliferation Cells Complete Androgen-Insensitivity Syndrome Consumption Curcumin Development Diethylnitrosamine Disease Epidemiology Female Food Generations Genome Growth Growth and Development function Hand Hemochromatosis Hepatic Hepatitis B Hepatitis B Virus Hepatitis C virus Hepatocarcinogenesis Hepatolenticular Degeneration Hereditary Disease Human In Vitro Incidence Ingestion Knock-out Knockout Mice Lead Liver Liver neoplasms Malignant Neoplasms Malignant neoplasm of liver Mediating Methods Molecular Mus Nude Mice Pathway interactions Patients Play Prevalence Primary Neoplasm Primary carcinoma of the liver cells Proliferating RNA Interference Risk Factors Role Sex Bias Small Interfering RNA Testing Testosterone Transgenic Mice Treatment Protocols Tumor Promoters Virus Wild Type Mouse Xenograft procedure cancer regression effective therapy hepatoma cell in vivo indexing knockout gene male mortality mouse model mutant neoplastic neoplastic cell promoter receptor function success tissue culture tumor tumor growth tumor xenograft tumorigenesis

项目摘要

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.

描述（由申请人提供）：原发性 HCC 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。导致肝癌的主要病因是乙型和丙型肝炎病毒（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见，本提案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，并探讨靶向AR治疗肝癌的可行性。肝癌。首先，将通过比较野生型、一般 AR 敲除（G-ARKO）和肝脏特异性 AR 敲除（G-ARKO）中致癌物、N,N-二乙基亚硝胺诱导的 HCC 发生和生长来研究 AR 在 HCC 发生和生长中的作用。通过测定L-ARKO)小鼠肝脏肿瘤发生率、肿瘤灶数量和大小的变化率，以及癌前灶生长、肿瘤细胞增殖和凋亡指标的组织化学比较。这些研究将通过生成携带 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 表达对原代细胞生长的影响，将进一步证实 AR 在这些小鼠模型中通过消融 AR 推断的肝脏肿瘤生长调节作用。原代培养物中野生型和 HBV 转基因小鼠的肿瘤细胞以及裸鼠中的肿瘤异种移植物。 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 的人类肝癌细胞（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 如何影响肝癌发生和进展的分子机制。公共相关性声明：该应用的成功不仅将提供有用的信息，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，并最终导致更有效的治疗方案这种致命的肿瘤疾病。