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. 2015 Jan 15:15:5.
doi: 10.1186/s12885-015-1008-4.

Clinicopathological significance of nuclear factor (erythroid-2)-related factor 2 (Nrf2) expression in gastric cancer

Yota Kawasaki  1 , Sumiya Ishigami  2 , Takaaki Arigami  3 , Yoshikazu Uenosono  4 , Shigehiro Yanagita  5 , Yasuto Uchikado  6 , Yoshiaki Kita  7 , Yuka Nishizono  8 , Hiroshi Okumura  9 , Akihiro Nakajo  10 , Yuko Kijima  11 , Kosei Maemura  12 , Shoji Natsugoe  13
Affiliations

Clinicopathological significance of nuclear factor (erythroid-2)-related factor 2 (Nrf2) expression in gastric cancer

Yota Kawasaki et al. BMC Cancer. .

Abstract

Background: 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. 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.

Methods: A 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 χ (2) 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.

Results: Nrf2 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).

Conclusions: Nrf2 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.

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Figures

Figure 1
Figure 1
Nuclear factor (erythroid-2)–related factor 2(Nrf2) expression in gastric carcinoma cell lines. Nrf2 protein expression in nuclear and cytoplasmic extracts of the gastric cell lines MKN74, MNK45, KATO-III, and NUGC4 was assayed by Western blotting. The blot was re-probed with anti-Lamin B1 and anti-α-Tubulin antibodies that were used as positive controls for the nucleus and cytoplasm, respectively. Nuclear and cytoplasmic fractions were clearly separated. The Nrf2 protein was identified mainly in the nucleus of all gastric cancer cell lines. Little Nrf2 was detected in the cytoplasm.
Figure 2
Figure 2
Immunostaining of nuclear factor (erythroid-2)–related factor 2 (Nrf2) in clinical gastric cancer samples. Representative immunostaining of Nrf2 in (a) Positive control, noncancerous placental tissue; (b) normal stomach tissue; (c – e) Gastric cancer tissues; (c) negative staining of Nrf2, (d) weak staining (+1) of Nrf2, (e) strong staining (+2) of Nrf2 (original magnification, ×400). Expression of Nrf2 in clinical samples. Immunostaining of Nrf2 (original magnification, ×400)
Figure 3
Figure 3
Postoperative outcomes of 175 gastric cancer patients according to nuclear factor (erythroid-2)–related factor 2 (Nrf2) expression. Kaplan Meier analysis of the postoperative outcomes of 175 gastric cancer patients according to Nrf2 expression. Survival curves were constructed for the 175 patients that were divided into Nrf2-positive and Nrf2-negative groups. The Nrf2-positive group had a significantly poorer outcome than the Nrf2-negative group (p < 0.01).
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