The UGT2A and 3A metabolizing enzymes and tobacco-related 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H&N癌症的易感性标志物，以识别这些癌症风险较高的烟草使用者。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（PAH）和烟草特异性亚硝胺（TSNAs））的解毒中起关键作用。初步数据表明，最少研究的代谢酶UGT 2A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性和剪接变体，从而可能改变这些靶位点的烟草致癌物的局部解毒。这些特征表明，UGT 2A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UGT 2A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UGT 2A和3A活性和表达通过基因型和剪接机制改变，并在烟草相关癌症的风险中发挥作用。该提案的具体目标是：（1）表征UGT 2A和3A酶的表达和活性;（2）检查UGT 2A和3A SNP对肺癌和H&N风险的重要性;以及（3）通过确定UGT 2A和3A剪接变体是否具有调节UGT缀合活性的功能，检查UGT 2A和3A剪接机制作为UGT 2A和3A调节的一种形式，可能会改变烟草相关癌症的风险。拟议的研究将使我们能够更好地了解UGT 2A和3A酶作为烟草相关癌症诱导易感性标志物的潜在作用，帮助我们确定针对性预防策略的受试者，并使我们能够评估差异剪接可能作为一种基因调控形式在癌症风险中发挥作用的创新概念。

 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.