Skip to main content
Top
Published in: Annals of Surgical Oncology 7/2014

01-07-2014 | Gastrointestinal Oncology

Nrf2 is Useful for Predicting the Effect of Chemoradiation Therapy on Esophageal Squamous Cell Carcinoma

Authors: Yota Kawasaki, MD, Hiroshi Okumura, MD, Yasuto Uchikado, MD, Yoshiaki Kita, MD, Ken Sasaki, MD, Tetsuhiro Owaki, MD, Sumiya Ishigami, MD, Shoji Natsugoe, MD

Published in: Annals of Surgical Oncology | Issue 7/2014

Login to get access

Abstract

Background

The transcription factor NF-E2-related factor 2 (Nrf2) was originally identified to be a critical regulator of intracellular antioxidants and phase II detoxification enzymes. Recent studies have shown that high Nrf2 expression gives cancer cells an advantage for survival from anticancer chemotherapy and radiation therapy. The aims of this retrospective study were to examine the expression of Nrf2 in biopsy specimens of esophageal squamous cell carcinoma (ESCC) and to evaluate whether such expression is useful for predicting the response to chemoradiation therapy (CRT).

Methods

A total of 46 patients with ESCC who received curative surgery after CRT from 1997 to 2011 were enrolled in the current study. Nrf2 expression in the biopsy specimens before CRT was examined immunohistochemically using anti-Nrf2 antibody. The correlations between Nrf2 expression and clinical factors and histological and clinical response to CRT were analyzed.

Results

The rate of Nrf2-positive expression was 39 %. Both clinically and histologically, significant correlations were found between positive Nrf2 expression and unfavorable response to CRT. Furthermore, Nrf2 was significantly correlated with clinical lymph node metastases and patients’ postoperative outcomes. Multivariate analysis showed that Nrf2 expression status was an independent prognostic factor.

Conclusions

Nrf2 expression was found to be closely related to the effect of CRT and could predict the CRT outcome in patients with ESCC.
Appendix
Available only for authorised users
Literature
1.
go back to reference Naunheim KS, Petruska P, Roy TS, Andrus CH, Johnson FE, Schlueter JM, et al. Preoperative chemotherapy and radiotherapy for esophageal carcinoma. J Thorac Cardiovasc Surg. 1992;103:887–93; discussion 893–5.PubMed Naunheim KS, Petruska P, Roy TS, Andrus CH, Johnson FE, Schlueter JM, et al. Preoperative chemotherapy and radiotherapy for esophageal carcinoma. J Thorac Cardiovasc Surg. 1992;103:887–93; discussion 893–5.PubMed
2.
go back to reference Baba M, Aikou T, Yoshinaka H, Natsugoe S, Fukumoto T, Shimazu H, et al. Long-term results of subtotal esophagectomy with three-field lymphadenectomy for carcinoma of the thoracic esophagus. Ann Surg. 1994;219:310–6.PubMedCentralPubMedCrossRef Baba M, Aikou T, Yoshinaka H, Natsugoe S, Fukumoto T, Shimazu H, et al. Long-term results of subtotal esophagectomy with three-field lymphadenectomy for carcinoma of the thoracic esophagus. Ann Surg. 1994;219:310–6.PubMedCentralPubMedCrossRef
3.
go back to reference Natsugoe S, Okumura H, Matsumoto M, Uchikado Y, Setoyama T, Yokomakura N, et al. Randomized controlled study on preoperative chemoradiotherapy followed by surgery versus surgery alone for esophageal squamous cell cancer in a single institution. Dis Esophagus. 2006;19:468–72.PubMedCrossRef Natsugoe S, Okumura H, Matsumoto M, Uchikado Y, Setoyama T, Yokomakura N, et al. Randomized controlled study on preoperative chemoradiotherapy followed by surgery versus surgery alone for esophageal squamous cell cancer in a single institution. Dis Esophagus. 2006;19:468–72.PubMedCrossRef
4.
go back to reference Zhang DD. Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev. 2006;38:769–89.PubMedCrossRef Zhang DD. Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev. 2006;38:769–89.PubMedCrossRef
5.
go back to reference 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;70:9095–105.PubMedCrossRef 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;70:9095–105.PubMedCrossRef
6.
go back to reference 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;93:14960–5.PubMedCentralPubMedCrossRef 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;93:14960–5.PubMedCentralPubMedCrossRef
7.
go back to reference 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;24:10941–53.PubMedCentralPubMedCrossRef 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;24:10941–53.PubMedCentralPubMedCrossRef
8.
go back to reference 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;275:16023–9.PubMedCrossRef 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;275:16023–9.PubMedCrossRef
9.
go back to reference 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;6:857–68.PubMedCrossRef 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;6:857–68.PubMedCrossRef
11.
go back to reference 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;135:1358–1368, e1–4.PubMed 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;135:1358–1368, e1–4.PubMed
12.
go back to reference Cho HY, Reddy SP, Kleeberger SR. Nrf2 defends the lung from oxidative stress. Antioxid Redox Signal. 2006;8:76–87.PubMedCrossRef Cho HY, Reddy SP, Kleeberger SR. Nrf2 defends the lung from oxidative stress. Antioxid Redox Signal. 2006;8:76–87.PubMedCrossRef
13.
go back to reference Kensler TW, Wakabayash N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol. 2007;47:89–116.CrossRef Kensler TW, Wakabayash N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol. 2007;47:89–116.CrossRef
15.
go back to reference 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;28:813–8.PubMedCrossRef 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;28:813–8.PubMedCrossRef
16.
go back to reference 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;68:1303–9.PubMedCrossRef 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;68:1303–9.PubMedCrossRef
17.
go back to reference 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;15:3423–32.PubMedCrossRef 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;15:3423–32.PubMedCrossRef
19.
go back to reference 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;9:336–46.PubMedCentralPubMedCrossRef 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;9:336–46.PubMedCentralPubMedCrossRef
20.
go back to reference 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;69:485–94.PubMedCrossRef 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;69:485–94.PubMedCrossRef
21.
go back to reference Chen Y, Jungsuwadee P, Vore M, Butterfield DA, Clair DKS. Collateral damage in cancer chemotherapy—Oxidative stress in nontargeted tissues. Mol Interv. 2007;7:147–56.PubMedCrossRef Chen Y, Jungsuwadee P, Vore M, Butterfield DA, Clair DKS. Collateral damage in cancer chemotherapy—Oxidative stress in nontargeted tissues. Mol Interv. 2007;7:147–56.PubMedCrossRef
22.
go back to reference 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;13:3875–82.PubMedCrossRef 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;13:3875–82.PubMedCrossRef
23.
go back to reference 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;260:96–108.PubMedCrossRef 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;260:96–108.PubMedCrossRef
24.
go back to reference Sobin LH, Wittekind Ch, eds. International union against cancer (UICC) TNM classification of malignant tumors (ICD-O C15). 6th ed. New York: Wiley. 2002. Sobin LH, Wittekind Ch, eds. International union against cancer (UICC) TNM classification of malignant tumors (ICD-O C15). 6th ed. New York: Wiley. 2002.
25.
go back to reference Tahara M, Ohtsu A, Hironaka S, Boku N, Ishikura S, Miyata Y, et al. Clinical impact of criteria for complete response (CR) of primary site to treatment of esophageal cancer. Jpn J Clin Oncol. 2005;35:316–23.PubMedCrossRef Tahara M, Ohtsu A, Hironaka S, Boku N, Ishikura S, Miyata Y, et al. Clinical impact of criteria for complete response (CR) of primary site to treatment of esophageal cancer. Jpn J Clin Oncol. 2005;35:316–23.PubMedCrossRef
26.
go back to reference Takubo K, Makuuchi H, Fujita H, Aikou T, Kajiyama Y, Kawano T, et al. Japanese classification of esophageal cancer, 10th ed. Part I. Esophagus. 2009;6:1–25. Takubo K, Makuuchi H, Fujita H, Aikou T, Kajiyama Y, Kawano T, et al. Japanese classification of esophageal cancer, 10th ed. Part I. Esophagus. 2009;6:1–25.
27.
go back to reference Takubo K, Makuuchi H, Fujita H, Aikou T, Kajiyama Y, Kawano T, et al. Japanese classification of esophageal cancer, 10th ed. Parts II and III. Esophagus. 2009;6:71–94. Takubo K, Makuuchi H, Fujita H, Aikou T, Kajiyama Y, Kawano T, et al. Japanese classification of esophageal cancer, 10th ed. Parts II and III. Esophagus. 2009;6:71–94.
28.
go back to reference 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;16:3743–53.PubMedCentralPubMedCrossRef 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;16:3743–53.PubMedCentralPubMedCrossRef
29.
go back to reference Boulikas T, Vougiouka M. Cisplatin and platinum drugs at the molecular level (review). Oncol Rep. 2003;10:1663–82.PubMed Boulikas T, Vougiouka M. Cisplatin and platinum drugs at the molecular level (review). Oncol Rep. 2003;10:1663–82.PubMed
30.
go back to reference Siddik ZH. Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene. 2003;22:7265–79.PubMedCrossRef Siddik ZH. Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene. 2003;22:7265–79.PubMedCrossRef
31.
go back to reference 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;29:1235–43.PubMedCentralPubMedCrossRef 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;29:1235–43.PubMedCentralPubMedCrossRef
32.
go back to reference 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:e99–105.PubMedCrossRef 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:e99–105.PubMedCrossRef
33.
go back to reference Okumura H, Natsugoe S, Matsumoto M, Yokomakura N, Uchikado Y, Takatori H, et al. The predictive value of p53, p53R2, and p21 for the effect of chemoradiation therapy on oesophageal squamous cell carcinoma. Br J Cancer. 2005;92:284–9.PubMedCentralPubMed Okumura H, Natsugoe S, Matsumoto M, Yokomakura N, Uchikado Y, Takatori H, et al. The predictive value of p53, p53R2, and p21 for the effect of chemoradiation therapy on oesophageal squamous cell carcinoma. Br J Cancer. 2005;92:284–9.PubMedCentralPubMed
Metadata
Title
Nrf2 is Useful for Predicting the Effect of Chemoradiation Therapy on Esophageal Squamous Cell Carcinoma
Authors
Yota Kawasaki, MD
Hiroshi Okumura, MD
Yasuto Uchikado, MD
Yoshiaki Kita, MD
Ken Sasaki, MD
Tetsuhiro Owaki, MD
Sumiya Ishigami, MD
Shoji Natsugoe, MD
Publication date
01-07-2014
Publisher
Springer US
Published in
Annals of Surgical Oncology / Issue 7/2014
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-014-3600-2

Other articles of this Issue 7/2014

Annals of Surgical Oncology 7/2014 Go to the issue