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

 描述(申请人提供)：吸烟和烟草使用是许多疾病的主要危险因素，包括肺癌和头颈部(H&N)癌。一个长期目标是建立肺癌和H&N癌的易感标记物，以确定烟草使用者患这些癌症的风险更高。UDP-糖基转移酶(UGT)对烟草和/或烟草烟雾中大量的致癌物，包括多环芳烃(PAHs)和烟草特有的亚硝胺(TSNAs)的解毒起着关键作用。初步数据表明，研究最少的代谢酶UGT2A和3A亚家族的成员在烟草靶组织中表达，包括肺和H&N，表现出对烟草致癌物的活性，并且存在改变其活性的多态和剪接变异体，从而潜在地改变了烟草致癌物在这些靶部位的局部解毒。这些特征表明，UGT2A和3A酶可能是烟草相关癌症的重要易感标记。这项建议的目的是验证我们的假设，即UGT2A和3A活性在烟草靶组织中烟草致癌物的局部解毒中起重要作用，并且UGT2A和3A的活性和表达通过基因和剪接机制改变，并在烟草相关癌症的风险中发挥作用。这项建议的具体目的是：(1)表征UGT2A和3A酶的表达和活性；(2)检测UGT2A和3A SNP对肺癌和H&N风险的重要性；以及(3)通过确定UGT2A和3A剪接变异体是否具有调节UGT结合活性的功能并潜在地改变与烟草相关的癌症风险，来研究UGT2A和3A剪接机制作为UGT2A和3A调控的一种形式。拟议的研究将使我们能够更好地了解UGT2A和3A酶作为烟草相关癌症诱导的易感标记的潜在作用，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一种在癌症风险中发挥作用的基因调控形式的创新概念。

 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.