COBRE P2: CYP1B1 INDUCTION IN TOBACCO-RELATED ORAL CARCINOGENESIS

COBRE P2：CYP1B1 诱导烟草相关口腔癌发生

• 批准号: 7959779
• 负责人: ANGELA C CHI
• 金额: $ 15.62万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959779
• 关键词: Apoptosis; Aromatic Polycyclic Hydrocarbons; Benzo(a)pyrene; CYP1A1 gene; CYP1B1 gene; Carcinogens; Cell physiology; Centers of Research Excellence; Computer Retrieval of Information on Scientific Projects Database; Cytochrome P450; DNA Adduction; Development; Disease; Enzymes; Exposure to; Extrahepatic; Funding; Gene Mutation; Genes; Genetic; Grant; Human; In Vitro; Institution; Intraepithelial Neoplasia; Investigation; Laboratories; Link; Malignant Neoplasms; Metabolic Activation; Morbidity - disease rate; Mutation; Oral health; Oral mucous membrane structure; Protein Isoforms; Relative (related person); Research; Research Personnel; Resources; Risk Factors; Site; Smoke; Smoker; Source; South Carolina; Squamous cell carcinoma; TP53 gene; Testing; Tissue Model; Tissues; Tobacco; Tobacco smoke; Tobacco use; United States; United States National Institutes of Health; adduct; men; mortality; mouth squamous cell carcinoma; oral carcinogenesis; oral tissue; tobacco exposure

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tobacco use is a well-established, major risk factor for development of oral squamous cell carcinoma (SCC)--a disease that represents one of the ten leading cancers in men in the United States and is associated with major morbidity and mortality. Chief among the carcinogens in tobacco smoke are the polycyclic aromatic hydrocarbons, including benzo[a]pyrene (BP). Metabolic activation of PAHs by cytochrome p450 (CYP) enzymes leads to DNA adduct formation, which presumably leads to cancer development via interaction with genes essential for regulating key cell functions such as apoptosis, proliferation, and differentiation. In particular, p53 gene mutations are among the most frequent genetic anomalies identified in oral SCC, and BP metabolites are known to form adducts at specific "hotspots" within the p53 gene. Expression of CYP enzymes by extrahepatic tissues--including oral mucosa--is not well characterized. In human oral mucosa, the major CYP enzyme isoforms induced by exposure to BP appear to be CYP1A1 and CYP1B1, and preliminary studies by our laboratory suggest that in smokers there is preferential induction of CYP1B1 over CYP1A1. The specific aims of this proposal are as follows: 1) to test the hypothesis that preferential CYP1B1 induction occurs during smoking-related transformation of normal oral mucosa into epithelial dysplasia and SCC and 2) to test the hypothesis that CYP1B1 induction in oral mucosa leads to metabolic activation of BP, resulting in DNA adduct formation and p53 gene mutations. The proposed research will constitute the first rigorously quantitative investigation of CYP1B1 versus CYP1A1 expression in human oral tissues relative to tobacco exposure. Furthermore, our studies will begin to unravel the underlying mechanisms linking BP metabolite-DNA adduct formation to oral carcinogenesis by using in vitro oral tissue models to demonstrate CYP1B1 induction by BP leads to DNA adduct formation and mutations at specific sites within the p53 gene.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 烟草使用是口腔鳞状细胞癌 (SCC) 发展的一个公认的主要危险因素，这种疾病是美国男性十大癌症之一，与主要发病率和死亡率相关。 烟草烟雾中的主要致癌物是多环芳烃，包括苯并[a]芘（BP）。 细胞色素 p450 (CYP) 酶对 PAH 的代谢激活导致 DNA 加合物形成，这可能通过与调节细胞凋亡、增殖和分化等关键细胞功能所必需的基因相互作用而导致癌症的发生。特别是，p53 基因突变是口腔鳞状细胞癌中最常见的遗传异常之一，并且已知 BP 代谢物会在 p53 基因内的特定“热点”处形成加合物。 肝外组织（包括口腔粘膜）的 CYP 酶表达尚不明确。 在人类口腔粘膜中，接触 BP 诱导的主要 CYP 酶亚型似乎是 CYP1A1 和 CYP1B1，我们实验室的初步研究表明，在吸烟者中，CYP1B1 比 CYP1A1 优先诱导。 该提案的具体目的如下：1）检验以下假设：在吸烟相关的正常口腔粘膜向上皮发育不良和鳞状细胞癌的转化过程中优先发生 CYP1B1 诱导；2）检验口腔粘膜中 CYP1B1 诱导导致 BP 代谢激活，导致 DNA 加合物形成和 p53 基因突变的假设。 拟议的研究将首次对人类口腔组织中与烟草暴露相关的 CYP1B1 与 CYP1A1 表达进行严格的定量研究。 此外，我们的研究将开始揭示 BP 代谢物-DNA 加合物形成与口腔癌发生之间的潜在机制，通过使用体外口腔组织模型来证明 BP 诱导 CYP1B1 导致 DNA 加合物形成和 p53 基因内特定位点的突变。