Evaluation of Nrf2 and MDR1/P-glycoprotein gene expression and protein levels in biopsy specimens of patients with and without gastric cancer

Abstract

Background: The efficacy of chemotherapeutic agents remains very poor in gastric cancer (GC) patients due to the development of multidrug resistance (MDR) phenotype. The nuclear factor erythroid 2-related factor 2 (Nrf2), is a pivotal transcriptional factor that regulates phase II detoxifying enzymes, antioxidants and efflux transporters including P-glycoprotein (P-gp). The aim of this study was to investigate the association of Nrf2 and P-gp and their correlations with clinicopathologic characteristics in GC patients. Methods: Nrf2 and MDR1/P-gp expressions in both mRNA and protein levels were examined by real-time PCR and immunohistochemical (IHC) staining respectively, in endoscopic biopsy samples from 60 GC patients compared with those expressions in non-GC individuals. Results: Our results showed that the positive rate of Nrf2 expression in GC patients (46.7%) was significantly higher than that in non-GC indivituals (11.7%) (p < 0.001, Mann–Whitney test), while there was no significant difference in P-gp expression. These results were confirmed by real-time PCR in mRNA level for both genes. Overexpression of Nrf2 was closely associated with tumor the size, histological grade, lymph node metastasis, and distant metastasis while P-gp upregulation was shown to be associated with the histological grade and tumor size (Chi-square, all p < 0.05). Nrf2 overexpression also play a key role in induction of P-gp as a drug efflux pump in GC biopsy samples (r = 0.55, p <0.001). 99 Conclusion: Our results suggest that therapeutic inhibition of Nrf2 expression can improve the efficacy of chemotherapeutic agents by down regulation of P-gp expression.