Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
Biomed Pharmacother. 2018 Jan;97:286-292. doi: 10.1016/j.biopha.2017.10.129. Epub 2017 Nov 6.
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 clinicopathological criteria in GC patients.Nrf2 and MDR1/P-gp expressions in both mRNA and protein levels were examined by real-time PCR and immunohistochemical staining (IHC) respectively, in endoscopic biopsy samples from60 GC patients compared with those expressions in non-GC individuals. Our results from IHC examinations revealed that Nrf2 expression in GC patients (46.7%) is markedly higher than that in non-GC individuals (11.7%) (p<0.001, Mann-Whitney test) which was confirmed by real-time PCR in mRNA levels. Induction of P-gp as a drug efflux pump, was associated with Nrf2 overexpression in these samples (r=0.55, p<0.001). There was also a strong correlation between Nrf2 overexpression and tumor size, histological grade, lymph node and distant metastasis while P-gp upregulation was shown to be associated only with the histological grade and tumor size (Chi-square, all p<0.05). Our results suggest that therapeutic inhibition of Nrf2 expression can improve the efficacy of chemotherapeutic agents for GC patients by down regulation of P-gp expression.
由于多药耐药（MDR）表型的发展，化疗药物在胃癌（GC）患者中的疗效仍然很差。核因子红细胞 2 相关因子 2（Nrf2）是一种关键的转录因子，可调节 II 相解毒酶、抗氧化剂和外排转运蛋白，包括 P 糖蛋白（P-gp）。本研究旨在探讨 Nrf2 和 P-gp 的相关性及其与 GC 患者临床病理标准的相关性。
通过实时 PCR 和免疫组织化学染色（IHC）分别检测 60 例 GC 患者内镜活检样本中 Nrf2 和 MDR1/P-gp 在 mRNA 和蛋白水平上的表达，并与非 GC 个体的表达进行比较。我们的 IHC 检查结果显示，GC 患者（46.7%）的 Nrf2 表达明显高于非 GC 个体（11.7%）（p<0.001，Mann-Whitney 检验），这在 mRNA 水平上通过实时 PCR 得到了证实。作为一种药物外排泵的 P-gp 的诱导与这些样本中 Nrf2 的过表达相关（r=0.55，p<0.001）。在这些样本中，Nrf2 过表达与肿瘤大小、组织学分级、淋巴结和远处转移之间也存在很强的相关性，而 P-gp 的上调仅与组织学分级和肿瘤大小相关（卡方检验，均 p<0.05）。
我们的研究结果表明，通过下调 P-gp 的表达来抑制 Nrf2 的表达，可能会提高化疗药物治疗 GC 患者的疗效。
