The UGT2A and 3A metabolizing enzymes and tobacco-related cancer risk

UGT2A 和 3A 代谢酶与烟草相关癌症风险

• 批准号: 9278174
• 负责人: Philip Lazarus
• 金额: $ 62.66万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9278174
• 关键词: Aerodigestive Tract; Affect; Alternative Splicing; Aromatic Polycyclic Hydrocarbons; Benzo(a)pyrene; Butanones; Cancer Patient; Carcinogen Metabolism; Carcinogens; Case-Control Studies; Cell Line; Characteristics; Data; Disease; Drug Metabolic Detoxication; Enzymes; Exhibits; Exons; Family; Funding; Gene Expression Regulation; Genes; Genetic Polymorphism; Genotype; Glucuronides; Glucuronosyltransferase; Goals; Head Cancer; Head and Neck Cancer; Head and neck structure; High-Risk Cancer; In Vitro; Individual; Individual Differences; Kinetics; Larynx; Liver; Lung; Lung Adenocarcinoma; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of lung; Microsomes; Neck Cancer; Nitrosamines; Organ; Pattern; Phase; Phenotype; Play; Predisposition; Prevention strategy; Proteins; Publishing; RNA Splicing; Regulation; Respiratory System; Respiratory tract structure; Risk; Risk Factors; Role; Site; Smoking; Specimen; Testing; Texas; Tissues; Tobacco; Tobacco smoke; Tobacco use; Tobacco-Associated Carcinogen; Tobacco-Related Carcinoma; Transcript; UGT1A1 gene; United States National Institutes of Health; Variant; base; cancer risk; carcinogenesis; cohort; enzyme activity; glycosyltransferase; human tissue; innovation; member; phenotypic biomarker; public health relevance; respiratory; validation studies

 DESCRIPTION (provided by applicant): Abstract Smoking and tobacco use are major risk factors for many diseases including lung and head and neck (H&N) cancer. A long term goal is to establish susceptibility markers for lung and H&N cancer to identify tobacco users at higher risk for these cancers. UDP-glycosyltransferase (UGT) enzymes play a critical role in the detoxification of many carcinogens abundant in tobacco and/or tobacco smoke including polycyclic aromatic hydrocarbons (PAHs) and tobacco-specific nitrosamines (TSNAs). Preliminary data suggest that members of the minimally-studied UGT2A and 3A sub-families of metabolizing enzymes are expressed in tobacco target tissues including lung and H&N, exhibit activity against tobacco carcinogens, and that polymorphic and splicing variants exist that alter their activity, thus potentially altering local detoxification of tobacco carcinogens at these targt sites. These characteristics suggest that UGT2A and 3A enzymes are potentially important susceptibility markers for tobacco-related cancers. The goal of this proposal is to test our hypothesis that UGT2A and 3A activity is important in the local detoxification of tobacco carcinogens in tobacco target tissues, and that UGT2A and 3A activities and expression are altered via genotypic and splicing mechanisms and play a role in risk of tobacco-related cancers. The specific aims of this proposal are to, (1) Characterize the expression and activity of UGT2A and 3A enzymes; (2) Examine the importance of UGT2A and 3A SNPs to risk for cancers of the lung and H&N; and (3) Examine UGT2A and 3A splicing mechanisms as a form of UGT2A and 3A regulation by determining whether UGT2A and 3A splice variants function to regulate UGT conjugating activities and potentially act to alter tobacco-related cancer risk. The proposed studies will enable us to better understand the potential role of the UGT2A and 3A enzymes as susceptibility markers for tobacco- related cancer induction, help us identify subjects for targeted prevention strategies, and enable us to evaluate the innovative concept that differential splicing may act as a form of gene regulation that plays a role in cancer risk.

 描述（由申请人提供）： 摘要 吸烟和烟草使用是许多疾病的主要危险因素，包括肺癌和头颈癌 (H&N)。长期目标是建立肺癌和头颈癌的易感性标记物，以识别较高水平的烟草使用者。 UDP-糖基转移酶 (UGT) 在烟草和/或烟草烟雾中丰富的许多致癌物（包括多环芳烃）的解毒中发挥着关键作用。 (PAH) 和烟草特有的亚硝胺 (TSNA) 初步数据表明，代谢酶 UGT2A 和 3A 亚家族的成员在包括肺和 H&N 在内的烟草靶组织中表达，表现出对抗烟草致癌物的活性。多态性和剪接的存在改变了它们的活性，从而可能改变烟草致癌物在这些目标位点的局部解毒作用。这些特征表明。 UGT2A 和 3A 酶是烟草相关癌症的潜在重要易感性标志物 该提案的目的是检验我们的假设，即 UGT2A 和 3A 活性在烟草靶组织中烟草致癌物的局部解毒中很重要，并且 UGT2A 和 3A 具有重要作用。活性和表达通过基因型和剪接机制发生改变，并在烟草相关癌症的风险中发挥作用。该提案的具体目的是：(1) 表征。 UGT2A 和 3A 酶的表达和活性；(2) 检查 UGT2A 和 3A SNP 对肺癌和 H&N 癌症风险的重要性；以及 (3) 检查 UGT2A 和 3A 剪接机制作为 UGT2A 和 3A 调节的一种形式；确定 UGT2A 和 3A 剪接变体是否具有调节 UGT 结合活性并可能改变烟草相关癌症风险的作用。我们可以更好地了解 UGT2A 和 3A 酶作为烟草相关癌症诱发的易感性标记的潜在作用，帮助我们确定有针对性的预防策略的对象，并使我们能够评估差异剪接可能作为基因的一种形式的创新概念在癌症风险中发挥作用的监管。