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Open Access 01-12-2015 | Research article

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

Authors: Yota Kawasaki, Sumiya Ishigami, Takaaki Arigami, Yoshikazu Uenosono, Shigehiro Yanagita, Yasuto Uchikado, Yoshiaki Kita, Yuka Nishizono, Hiroshi Okumura, Akihiro Nakajo, Yuko Kijima, Kosei Maemura, Shoji Natsugoe

Published in: BMC Cancer | Issue 1/2015

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 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.

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.

Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55(2):74–108.CrossRefPubMed

Brenner H, Rothenbacher D, Arndt V. Epidemiology of stomach cancer. Methods Mol Biol. 2009;472:467–77.CrossRefPubMed

Warneke VS, Behrens HM, Hartmann JT, Held H, Becker T, Schwarz NT, et al. Cohort study based on the seventh edition of the TNM classification for gastric cancer: proposal of a new staging system. J Clin Oncol. 2011;29(17):2364–71.CrossRefPubMed

Lagarde SM, ten Kate FJ, Reitsma JB, Busch OR, van Lanschot JJ. Prognostic factors in adenocarcinoma of the esophagus or gastroesophageal junction. J Clin Oncol. 2006;24(26):4347–55.CrossRefPubMed

Ni J, Mei M, Sun L. Oxidative DNA damage and repair in chronic atrophic gastritis and gastric cancer. Hepatogastroenterology. 2012;59(115):671–5.PubMed

Engin AB, Karahalil B, Engin A, Karakaya AE. DNA repair enzyme polymorphisms and oxidative stress in a Turkish population with gastric carcinoma. Mol Biol Rep. 2011;38(8):5379–86.CrossRefPubMed

Venugopal R, Jaiswal AK. 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 U S A. 1996;93(25):14960–5.CrossRefPubMedPubMedCentral

Zhang DD. Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev. 2006;38(4):769–89.CrossRefPubMed

Shibata T, Saito S, Kokubu A, Suzuki T, Yamamoto M, Hirohashi S. Global downstream pathway analysis reveals a dependence of oncogenic NF-E2-related factor 2 mutation on the mTOR growth signaling pathway. Cancer Res. 2010;70(22):9095–105.CrossRefPubMed

10.

Zhang DD, Lo SC, Cross JV, Templeton DJ, Hannink M. Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol. 2004;24(24):10941–53.CrossRefPubMedPubMedCentral

11.

Ishii T, Itoh K, Takahashi S, Sato H, Yanagawa T, Katoh Y, et al. Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem. 2000;275(21):16023–9.CrossRefPubMed

12.

Katoh Y, Itoh K, Yoshida E, Miyagishi M, Fukamizu A, Yamamoto M. Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. Genes Cells. 2001;6(10):857–68.CrossRefPubMed

13.

Banning A, Deubel S, Kluth D, Zhou Z, Brigelius-Flohe R. The GI-GPx gene is a target for Nrf2. Mol Cell Biol. 2005;25(12):4914–23.CrossRefPubMedPubMedCentral

14.

Ohta T, Iijima K, Miyamoto M, Nakahara I, Tanaka H, Ohtsuji M, et al. Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth. Cancer Res. 2008;68(5):1303–9.CrossRefPubMed

15.

Kim HR, Kim S, Kim EJ, Park JH, Yang SH, Jeong ET, et al. Suppression of Nrf2-driven heme oxygenase-1 enhances the chemosensitivity of lung cancer A549 cells toward cisplatin. Lung Cancer. 2008;60(1):47–56.CrossRefPubMed

16.

Kim JH, Bogner PN, Ramnath N, Park Y, Yu J, Park YM. 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;13(13):3875–82.CrossRefPubMed

17.

Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005;97(5):339–46.CrossRefPubMed

18.

Stacy DR, Ely K, Massion PP, Yarbrough WG, Hallahan DE, Sekhar KR, et al. Increased expression of nuclear factor E2 p45-related factor 2 (NRF2) in head and neck squamous cell carcinomas. Head Neck. 2006;28(9):813–8.CrossRefPubMed

19.

Shibata T, Kokubu A, Gotoh M, Ojima H, Ohta T, Yamamoto M, et al. Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer. Gastroenterology. 2008;135(4):1358–68. 1368 e1351-1354.CrossRefPubMed

20.

Lau A, Villeneuve NF, Sun Z, Wong PK, Zhang DD. Dual roles of Nrf2 in cancer. Pharmacol Res. 2008;58(5–6):262–70.CrossRefPubMedPubMedCentral

21.

Solis LM, Behrens C, Dong W, Suraokar M, Ozburn NC, Moran CA, et al. Nrf2 and Keap1 Abnormalities in Non-Small Cell Lung Carcinoma and Association with Clinicopathologic Features. Clin Cancer Res. 2010;16(14):3743–53.CrossRefPubMedPubMedCentral

22.

Ma X, Zhang J, Liu S, Huang Y, Chen B, Wang D. Nrf2 knockdown by shRNA inhibits tumor growth and increases efficacy of chemotherapy in cervical cancer. Cancer Chemother Pharmacol. 2012;69(2):485–94.CrossRefPubMed

23.

Wang J, Zhang M, Zhang L, Cai H, Zhou S, Zhang J, et al. Correlation of Nrf2, HO-1, and MRP3 in gallbladder cancer and their relationships to clinicopathologic features and survival. J Surg Res. 2010;164(1):e99–105.CrossRefPubMed

24.

Kim YR, Oh JE, Kim MS, Kang MR, Park SW, Han JY, et al. Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin. J Pathol. 2010;220(4):446–51.CrossRefPubMed

25.

Grogan TM, Fenoglio-Prieser C, Zeheb R, Bellamy W, Frutiger Y, Vela E, et al. Thioredoxin, a putative oncogene product, is overexpressed in gastric carcinoma and associated with increased proliferation and increased cell survival. Hum Pathol. 2000;31(4):475–81.CrossRefPubMed

26.

Hu XF, Yao J, Gao SG, Wang XS, Peng XQ, Yang YT, et al. Nrf2 overexpression predicts prognosis and 5-fu resistance in gastric cancer. Asian Pac J Cancer Prev. 2013;14(9):5231–5.CrossRefPubMed

27.

Li W, Kong AN. Molecular mechanisms of Nrf2-mediated antioxidant response. Mol Carcinog. 2009;48(2):91–104.CrossRefPubMedPubMedCentral

28.

Zhang P, Singh A, Yegnasubramanian S, Esopi D, Kombairaju P, Bodas M, et al. Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth. Mol Cancer Ther. 2010;9(2):336–46.CrossRefPubMedPubMedCentral

29.

Homma S, Ishii Y, Morishima Y, Yamadori T, Matsuno Y, Haraguchi N, et al. Nrf2 enhances cell proliferation and resistance to anticancer drugs in human lung cancer. Clin Cancer Res. 2009;15(10):3423–32.CrossRefPubMed

30.

Wang XJ, Sun Z, Villeneuve NF, Zhang S, Zhao F, Li Y, et al. Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis. 2008;29(6):1235–43.CrossRefPubMedPubMedCentral

31.

Cho JM, Manandhar S, Lee HR, Park HM, Kwak MK. Role of the Nrf2-antioxidant system in cytotoxicity mediated by anticancer cisplatin: implication to cancer cell resistance. Cancer Lett. 2008;260(1–2):96–108.CrossRefPubMed

32.

Kensler TW, Wakabayash N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2007;47:89–116.CrossRefPubMed

33.

Chen Y, Jungsuwadee P, Vore M, Butterfield DA, Clair DKS. Collateral damage in cancer chemotherapy - Oxidative stress in nontargeted tissues. Mol Interv. 2007;7(3):147–56.CrossRefPubMed

Title: Clinicopathological significance of nuclear factor (erythroid-2)-related factor 2 (Nrf2) expression in gastric cancer
Authors: Yota Kawasaki
Sumiya Ishigami
Takaaki Arigami
Yoshikazu Uenosono
Shigehiro Yanagita
Yasuto Uchikado
Yoshiaki Kita
Yuka Nishizono
Hiroshi Okumura
Akihiro Nakajo
Yuko Kijima
Kosei Maemura
Shoji Natsugoe
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-015-1008-4

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Abstract

Background

Methods

Results

Conclusions

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