Expressão de genes da família CYP450 e outras oxigenases em câncer de cavidade oral

Abstract

Introduction: Susceptibility to enviromental agents as well as its adverse effects health depend on the personal genetic profile. Some individuals can present increased risk to develop cancer due to differences in biometabolism. Changes in the biotransformation mechanism of endogenous and exogenous compounds by oxidation reactions may be related to the tumorigenesis process. Differential expression of the genes involved in this xenobiotic metabolizing, such as cytochrome P450 (CYP) family members and others oxygenases, can change the activation process of toxic agents and lead to the oral cavity tumor development. Therefore, the individual differences of gene expression of this pathway associated to smoking and drinking can present significant risk factor for neoplasia. Objective: To identify the pattern of the gene expression involved in the biotransformation mechanism of endogenous and xenobiotic compounds in oral cavity tumors, aiming at identifing susceptibility biomarkers to this cancer type. Methods: Eight tissue samples of patients with oral cavity squamous cell carcinoma and eight adjacent non-tumor tissue samples were used. Expression of 92 genes CYP450 family and other oxygenases was quantifited by duplicate reactions of real time qPCR using “TaqMan® Array Human CYP450 and other Oxygenases 96-well fast plate” (Applied Biosystems). For statistical analysis was performed D'Agostino & Pearson omnibus normality test, followed by One-sample T test (data that showed normal distribution), and Wilcoxon signed rank test (data that did not present normal distribution) using GraphPad Prism v.5 program. Correction for multiple testing of Benjamini-Hochberg False Discovery Rate was applied to correct false positives. Bioinformatics tool was used to understand the biological system functions and to associate the differential expressed genes with specific metabolic pathways. Results: Of the 96 investigated genes involved in biotransformation mechanism (excepting the four reference genes), 12 genes showed differential expression in carcinoma tissue of oral cavity squamous cell type compared to non-tumor tissue (p<0.05). Only CYP27B1 gene presented increased expression in the oral cavity tumors, whereas CYP27A1, CYP2E1, CYP2R1, CYP2J2, CYP2U1, CYP4F12, CYP4X1, PTGIS, ALOX12, CYP4B1 and MAOB genes showed reduced expression. After correction by multiple tests, only PTGIS gene presented differential expression, with reduced expression. After data survey bioinformatics, five proteins were observed involved in the metabolism of arachidonic acid associated with important inflammatory processes in carcinogenesis (CYP2E1, CYP2J2, CYP2U1, ALOX12 and PTGIS). Conclusion: Genes involved in the carcinogens oxidation reactions showed differential expression in tumors of oral cavity. The enzymes encoded by these genes play an important role in the arachidonic acid metabolism, only pathway related to PTGIS enzyme, significant after analysis of statistical correction. The arachidonic acid and/or metabolites derived this pathway may modulate others metabolisms in which these enzymes are involved and can influence the regulation of important physiological mechanisms in tumorigenesis process.