Available online 15 November 2022

AbstractBackground

Gastric cancer is one of the leading causes of cancer-related death, and many researchers are focused on the discovery and use of different biomarkers in prognosis prediction. The use of Nrf2 as a prognostic marker in patients with gastric cancer remains controversial. In this study, we evaluated the expression of Nrf2 protein in gastric adenocarcinoma.

Patients and methods

A total of 86 patients who underwent gastric resection and D2 lymph node dissection due to gastric adenocarcinoma were included. Clinicopathological characteristics, such as age, gender, gastrectomy type, pathologic T (pT) and N (pN) stages, tumor grade, tumor type per Lauren’s classification, presence of lymphovascular invasion, and Nrf2 expression were evaluated.

Results

While pT, pN, and Nrf-2 expression were found to be negative prognostic predictors for overall survival in one-way analysis of variance, Nrf-2 expression was the only significant negative prognostic predictor in multivariance analysis. pT, pN, diffuse type, high tumor grade, and Nrf-2 expression significantly affected overall survival in Kaplan-Meier survival analyses (p = 0.02, p = 0.03, p < 0.01, p = 0.027, and p = 0.001, respectively).

Conclusions

Our findings support that Nrf2 is a prognostic marker in patients with gastric adenocarcinoma. Anti-Nrf2 therapy options should be investigated to improve prognosis in gastric cancer patients.

Introduction

Gastric cancer ranks fourth among the most frequent cancers in the world and is the second most common cause of cancer-related deaths [1]. While surgical resection and lymph node dissection are the main treatment options for gastric cancer, surgery also provides information for staging and prognosis prediction [2]. Although significant progress has been made in the diagnosis and treatment of gastric cancer in recent years, there has been relatively less improvement in overall survival, indicating an urgent need to provide a better understanding of the biological aspects of cancer [3].

Oxidative phosphorylation is the major mechanism for energy production in the cell. However, the energy released during oxidative phosphorylation leads to the generation of free oxygen radicals. These radicals are removed via reduction by antioxidant mechanisms, such as glutathione peroxidase and superoxide dismutase. However, if a large amount of free oxygen radicals accumulates in the cells, these can damage DNA, and if the damage cannot be repaired or damaged cells cannot undergo apoptosis, mutations can accumulate and cause malignant transformation. Increased oxygen radical related DNA damage has been shown to result in malignant transformation of gastric mucosa [4], and oxidative stress is considered to have an important role in the development of gastric cancer [5]. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates the expression of cellular antioxidants and, therefore, contributes to cellular defense against oxidative stress [6]. The overexpression of Nrf2 in tumor cells has been associated with worse prognosis and chemoresistance [7]. There is limited data regarding the clinicopathological characteristics of Nrf2 expressing gastric carcinomas in the available literature. Hence, the aim of this study was to investigate the prognostic impact of Nrf2 expression in gastric adenocarcinoma.

Section snippetsPatient selection

This retrospective study was conducted with the approval of the institutional ethics committee. A total of 144 patients that underwent gastric resection due to gastric cancer in our center between February 2008 and February 2017 were evaluated for eligibility to participate in this study. The eligibility criteria were as follows: (1) not receiving neoadjuvant chemotherapy, (2) no history of gastrectomy or other malignancies, (3) not having stage 4 gastric cancer, (4) pathologically negative

Results

Of the 86 patients, 16 (18.6 %) were female and 70 (81.4 %) were male. The mean age was 65.9 years (range, 38–87 years). The mean follow-up was 30.69 months (range, 2–115 months). Less than half of the cases (46.5 %) showed Nrf2 expression. There was no statistically significant difference between the cases with and without Nrf2 staining in terms of age, gender, type of gastrectomy (total or distal gastrectomy), pT, pN and pTNM stages, tumor type, tumor grade, and LVI parameters (Table 1). A

Discussion

In this retrospective study, we found that Nrf2 expression had a significantly negative impact on the prognosis of patients with gastric adenocarcinoma. Similar to our findings, Kawasaki et al. have also observed a worse prognosis in Nrf2 positive gastric carcinoma patients [8], and Nrf2 expression has been suggested to be an independent prognostic factor in gastric carcinoma [8], [9]. Nrf2 is a transcription factor that enhances the activity of antioxidant response genes to reduce the effects

Declaration of competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References (34)A.B. Engin et al.DNA repair enzyme polymorphisms and oxidative stress in a Turkish population with gastric carcinoma

Mol Biol Rep

(2011)

D. Chen et al.ARF–NRF2: A new checkpoint for oxidative stress responses?

Mol Cell Oncol

(2018)

Y. Kawasaki et al.Clinicopathological significance of nuclear factor (erythroid-2)-related factor 2 (Nrf2) expression in gastric cancer

BMC Cancer

(2015)

X.-F. Hu et al.Nrf2 overexpression predicts prognosis and 5-FU resistance in gastric cancer

Asian Pac J Cancer Prev

(2013)

R. Venugopal et al.Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD (P) H: quinone oxidoreductase1 gene

Proc Natl Acad Sci

(1996)

T. Ohta et al.Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth

Cancer Res

(2008)

J.-H. Kim et al.Elevated peroxiredoxin 1, but not NF-E2–related factor 2, is an independent prognostic factor for disease recurrence and reduced survival in stage I non–small cell lung cancer

Clin Cancer Res

(2007)

View full text

© 2022 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.