Gender Disparity in Bladder Cancer and Chemopreventive Intervention

膀胱癌的性别差异和化学预防干预

基本信息

批准号：
9198759
负责人：
YUESHENG ZHANG
金额：
$ 32.53万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-14 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9198759
关键词：
2-Acetylaminofluorene 4-biphenylamine Androgens Animal Model Aromatic Amines Bladder Bladder Tissue Carcinogen exposure Carcinogens Castration Cell model Cells Chemopreventive Agent Chronic Code Cultured Cells DNA Adducts DNA Damage Data Development Dietary Phytochemical Drug Metabolic Detoxication Environmental Carcinogens Enzymes Estrone Excretory function Exposure to Family Female Gender Gene Expression Genes Genetic Polymorphism Genetic Transcription Glucuronic Acids Glucuronides Glucuronosyltransferase Hepatic Hepatocyte Human Incidence Intervention Knowledge Lead Liver Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of urinary bladder Metabolic Activation Molecular Mus Parents Phase Physiological Play Predisposition Preventive Protein Isoforms Pseudogenes Publishing Race Risk Factors Role Signal Transduction Single Nucleotide Polymorphism Source Sulforaphane Testing Tobacco smoke Transgenic Mice UGT1A1 gene United States Urine Variant Wild Type Mouse Woman bladder cancer prevention carcinogenesis carcinogenicity chemical carcinogenesis disorder prevention expectation gender disparity in vivo male men mouse model novel strategies overexpression public health relevance urinary

项目摘要

DESCRIPTION (provided by applicant): Bladder cancer (BC) is the 4th most common cancer in men, but BC incidence is nearly 4 fold higher in men than in women across race; the underlying cause is not understood. Lack of such knowledge impedes progress in BC prevention. On the basis of our published and unpublished data, we hypothesize that hepatic UDP-glucuronosyltransferase 1A3 (UGT1A3) is a key determinant of the gender disparity in human BC development through converting androgen signal to increased urinary delivery of arylamine carcinogens to bladder tissue. Arylamines, 4-aminobiphenyl (ABP) in particular, are the main cause of human BC. We also hypothesize that sulforaphane (SF), a common dietary phytochemical, can block UGT1A3 from promoting arylamine-induced bladder carcinogenesis by boosting cytoprotective defense in the bladder. These hypotheses will be examined in four specific aims using complementary approaches of cultured cells and transgenic mouse models. Aim 1 is to test our hypothesis that liver UGT1A3 is a key molecule that determines the gender disparity in BC development. Wild-type mice and UGT1A3 transgenic mice (liver- specific and androgen-independent expression) will be compared for ABP-induced bladder carcinogenesis. Comparison will also be made between mice with and without castration. Another carcinogen 2- acetylaminofluorene (2-AAF) will be used to rule out ABP-specific effects. Aim 2 is to assess the impact of UGT1A3 polymorphism on its catalytic activity toward ABP and 2-AAF and on the susceptibility of bladder cells and liver cells to DNA damage induced by ABP and 2-AAF. Six single nucleotide polymorphisms occur in UGT1A3 gene. All the polymorphic variants together with the wild-type gene will be evaluated. Aim 3 is to test our hypothesis that SF can block UGT1A3 from promoting bladder carcinogenesis by stimulating cytoprotective defense against arylamine carcinogens (ABP and 2-AAF) in the bladder, without modulating UGT1A3 in the liver. Non-interference of liver UGT1A3 may be desirable, since this enzyme may be physiologically important, such as metabolizing estrone. SF is a promising cancer-preventive agent and is selectively delivered to bladder tissue through urinary excretion. Two animal models will be used to test the hypothesis, including the UGT1A3 mouse model described above and the Tg-UGT1 mouse model (mice carry both the coding and the regulatory sequences of the human UGT1A3 gene). Aim 4 is to confirm that UGT1A3 is transcriptionally stimulated by androgen in vivo and to elucidate the molecular mechanism by which androgen stimulates UGT1A3. This will be accomplished by using both cell models and the Tg-UGT1 mouse model. Impact: The proposed studies are expected to lead to the elucidation of the molecular basis of the gender disparity in BC and the development of new strategy for effective prevention of this disease.

描述（由申请人提供）：膀胱癌 (BC) 是男性第四大常见癌症，但不同种族的男性 BC 发病率比女性高近 4 倍；根本原因尚不清楚。缺乏此类知识会阻碍 BC 预防的进展。根据我们已发表和未发表的数据，我们假设肝脏 UDP-葡萄糖醛酸基转移酶 1A3 (UGT1A3) 通过将雄激素信号转化为增加尿中芳胺致癌物向膀胱组织的输送，是人类 BC 发展中性别差异的关键决定因素。芳胺，特别是 4-氨基联苯 (ABP)，是人类 BC 的主要原因。我们还假设萝卜硫素（SF）是一种常见的膳食植物化学物质，可以通过增强膀胱的细胞保护防御来阻止 UGT1A3 促进芳基胺诱导的膀胱癌发生。这些假设将使用培养细胞和转基因小鼠模型的互补方法在四个具体目标中进行检验。目标 1 是检验我们的假设，即肝脏 UGT1A3 是决定 BC 发展性别差异的关键分子。将比较野生型小鼠和 UGT1A3 转基因小鼠（肝脏特异性和雄激素非依赖性表达）的 ABP 诱导的膀胱癌发生。还将对阉割和未阉割的小鼠进行比较。另一种致癌物 2-乙酰氨基芴 (2-AAF) 将用于排除 ABP 特异性影响。目的 2 是评估 UGT1A3 多态性对其对 ABP 和 2-AAF 的催化活性以及对膀胱细胞和肝细胞对 ABP 和 2-AAF 诱导的 DNA 损伤的敏感性的影响。 UGT1A3基因存在6个单核苷酸多态性。所有多态性变体以及野生型基因都将被评估。目标 3 是检验我们的假设，即 SF 可以通过刺激膀胱中针对芳基胺致癌物（ABP 和 2-AAF）的细胞保护性防御来阻止 UGT1A3 促进膀胱癌发生，而不调节肝脏中的 UGT1A3。肝脏 UGT1A3 不受干扰可能是理想的，因为这种酶可能具有重要的生理作用，例如代谢雌酮。 SF 是一种有前途的癌症预防剂，通过尿液排泄选择性地输送到膀胱组织。将使用两种动物模型来检验该假设，包括上述 UGT1A3 小鼠模型和 Tg-UGT1 小鼠模型（小鼠同时携带人类 UGT1A3 基因的编码序列和调控序列）。目的4是确认UGT1A3在体内受到雄激素的转录刺激，并阐明雄激素刺激UGT1A3的分子机制。这将通过使用细胞模型和 Tg-UGT1 小鼠模型来完成。影响：拟议的研究预计将阐明 BC 性别差异的分子基础，并制定有效预防这种疾病的新策略。