COBRE P2: CYP1B1 INDUCTION IN TOBACCO-RELATED ORAL CARCINOGENESIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 吸烟是患口腔鳞状细胞癌(SCC)的一个公认的主要风险因素。口腔鳞状细胞癌是美国男性十大主要癌症之一，与主要发病率和死亡率有关。烟草烟雾中的主要致癌物质是多环芳烃，包括苯并[a]芘(BP)。细胞色素P450(CYP)酶对多环芳烃的代谢激活导致DNA加合物的形成，DNA加合物可能通过与调节细胞凋亡、增殖和分化等关键细胞功能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，已知BP代谢物在P53基因的特定“热点”形成加合物。CYP酶在肝外组织--包括口腔粘膜--的表达还不是很好。在人类口腔粘膜中，暴露于BP所诱导的主要细胞色素P450酶同工酶是细胞色素P1A1和细胞色素P1B1，我们实验室的初步研究表明，在吸烟者中，细胞色素P1B1的诱导优先于细胞色素P1A1。这一建议的具体目的是：1)检验在吸烟相关的正常口腔粘膜向上皮异型增生和鳞癌转化过程中优先诱导CYP1B1的假设；2)检验口腔粘膜中的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。这项拟议的研究将构成第一次严格定量研究与烟草暴露相关的人类口腔组织中细胞色素P1B1和细胞色素P1A1的表达。此外，我们的研究将通过使用体外口腔组织模型来揭示BP代谢物-DNA加合物形成与口腔癌发生之间的潜在机制，以证明BP诱导的CYP1B1会导致DNA加合物形成和p53基因特定位置的突变。

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.