Abstract
BackgroundThe transcription factor nuclear factor (erythroid-2)–related factor 2 (Nrf2) was originally identified as a critical regulator of intracellular anti-oxidants and of phase II detoxification enzymes through its transcriptional up-regulation of many anti-oxidant response element (ARE)-containing genes. Nrf2 protects not only normal cells but also cancer cells from cellular stress, and enhances cancer cell survival. Some studies have shown that Nrf2 expression in cancer patients has clinical significance. However, there has been no comprehensive analysis of the nuclear expression level of Nrf2 in gastrointestinal cancer cells. In this study we aimed to immunohistochemically evaluate the expression of Nrf2, and to assess its clinical significance in gastric cancer.MethodsA total of 175 gastric cancer patients who received R0 gastrectomy with standard lymph node dissection were enrolled. We immunohistochemically evaluated Nrf2 expression in the paraffin-embedded surgically resected specimens of these 175 patients. Group differences were analyzed using the χ2 test, Fisher’s exact test, and the Mann–Whitney U test. Associations between Nrf2 expression and clinicopathological features, including clinical outcome, were assessed using univariate and multivariate analyses, and Kaplan-Meier curves with the log-rank test, respectively.ResultsNrf2 immunoreactivity was predominantly identified in the nucleus of gastric cancer cells. Nrf2 positivity was closely associated with tumor size, tumor depth, lymph node metastases, lymphovascular invasion, histology and stage (p < 0.05 for all). A log-rank test indicated that the overall survival of the Nrf2-positive group was significantly poorer than that of the Nrf2-negative group (p < 0.01). And, positive Nrf2 expression was significantly associated with resistance to 5FU-based adjuvant chemotherapy (p = 0.024).ConclusionsNrf2 expression was positively associated with aggressive tumor behavior in gastric cancer. This result suggests that Nrf2 expression in gastric cancer is a potential indicator of worse prognosis.
Highlights
The transcription factor nuclear factor–related factor 2 (Nrf2) was originally identified as a critical regulator of intracellular anti-oxidants and of phase II detoxification enzymes through its transcriptional up-regulation of many anti-oxidant response element (ARE)-containing genes
nuclear factor (erythroid-2)–related factor 2 (Nrf2) positive expression was significantly associated with gender, tumor size, tumor depth, lymph node metastases, lymphovascular invasion, histologic classification and clinical stage of gastric cancer
It has been speculated that persistent nuclear expression of Nrf2 in gastric cancer cell lines results in the production of antioxidants, which confer on these cancer cell lines a high ability to resist reactive oxygen species (ROS)
Summary
The transcription factor nuclear factor (erythroid-2)–related factor 2 (Nrf2) was originally identified as a critical regulator of intracellular anti-oxidants and of phase II detoxification enzymes through its transcriptional up-regulation of many anti-oxidant response element (ARE)-containing genes. Some studies have shown that Nrf expression in cancer patients has clinical significance. In this study we aimed to immunohistochemically evaluate the expression of Nrf, and to assess its clinical significance in gastric cancer. The transcription factor nuclear factor (erythroid-2)– related factor 2 (Nrf2), which is a basic redox-sensitive bZIP transcription factor, was originally identified as a critical regulator of intracellular antioxidants and of phase II detoxification enzymes through the transcriptional upregulation of many antioxidant response element (ARE) -containing genes [7,8,9]. Nrf is bound to the kelch-like ECH-associated protein 1 (Keap1), a cul3-based E3 ubiquitin ligase adapter that regulates Nrf ubiquitination and proteasome-dependent degradation [10]
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