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 On the basis of our published and unpublished data, we hypothesize that hepatic UDP-glucuronosyltransferase 1A3 (UGT1A3) is a key determinant of the gender disparity in human BC development through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）是男性中第四大癌症，但卑诗省的发生率的男性比在种族中的女性高4倍。根本原因尚不理解。缺乏这种知识阻碍了卑诗省预防的进展。根据我们发布和未发表的数据，我们假设肝UDP葡萄糖基糖基转移酶1A3（UGT1A3）是人类BC发展中性别差异的关键决定因素，通过将雄激素信号转化为增加芳基胺癌至Bladder consectue的尿素递送。芳基胺，特别是4-氨基苯基（ABP），是人类BC的主要原因。我们还假设，一种常见的饮食植物化学化学硫烷（SF）可以阻止UGT1A3通过促进膀胱中的细胞保护剂来阻止UGT1A3促进芳胺诱导的膀胱致癌。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特定目标中进行检查。目的1是检验我们的假设，即肝UGT1A3是决定卑诗省发展中性别差异的关键分子。将比较野生型小鼠和UGT1A3转基因小鼠（肝特异性和雄激素独立的表达），以用于ABP诱导的膀胱癌变。也将在没有cast割和没有cast割的小鼠之间进行比较。另一种2-乙酰胺（2-AAF）将用于排除ABP特异性效应。 AIM 2是评估UGT1A3多态性对其对ABP和2-AAF的催化活性以及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基因中发生了六个单核苷酸多态性。将评估所有多态性变体以及野生型基因。 AIM 3是测试我们的假设，即SF可以通过刺激针对膀胱中的芳基胺致癌物（ABP和2-AAF）的细胞保护剂防御来阻止UGT1A3促进膀胱致癌作用，而无需调节肝脏中的UGT1A3。肝UGT1A3的不干预可能是可取的，因为该酶在生理上可能很重要，例如代谢雌酮。 SF是一种有前途的预防剂，通过尿液排泄有选择地将其传递到膀胱组织。将使用两种动物模型来检验假设，包括上述的UGT1A3小鼠模型和TG-ugt1小鼠模型（小鼠携带人类UGT1A3基因的编码和调节序列）。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小鼠模型来实现。影响：拟议的研究预计将导致卑诗省性别差异的分子基础，并制定有效预防该疾病的新战略。