title: Clinicopathological significance of nuclear factor (erythroid-2)-related factor 2 (Nrf2) expression in gastric 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.
authors.affiliation: Department of Digestive Surgery, Breast and Thyroid surgery Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, 890-8520, Japan. gekayota@gmail.com.
authors.forename: Yota
authors.initials: Y
authors.lastname: Kawasaki
authors.affiliation: Department of Digestive Surgery, Breast and Thyroid surgery Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, 890-8520, Japan. igeka@m2.kufm.kagoshima-u.ac.jp.
authors.forename: Sumiya
authors.initials: S
authors.lastname: Ishigami
authors.affiliation: Department of Digestive Surgery, Breast and Thyroid surgery Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, 890-8520, Japan. arigami@m.kufm.kagoshima-u.ac.jp.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Arigami
authors.affiliation: Department of Digestive Surgery, Breast and Thyroid surgery Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, 890-8520, Japan. uenosono@m3.kufm.kagoshima-u.ac.jp.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Uenosono
authors.affiliation: Department of Digestive Surgery, Breast and Thyroid surgery Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, 890-8520, Japan. s0810y2003@yahoo.co.jp.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Yanagita
authors.affiliation: Department of Digestive Surgery, Breast and Thyroid surgery Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, 890-8520, Japan. just-u@m.kufm.kagoshima-u.ac.jp.
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Uchikado
authors.affiliation: Department of Digestive Surgery, Breast and Thyroid surgery Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, 890-8520, Japan. north-y@m.kufm.kagoshima-u.ac.jp.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kita
authors.affiliation: Department of Digestive Surgery, Breast and Thyroid surgery Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, 890-8520, Japan. yuka-n@m3.kufm.kagoshima-u.ac.jp.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nishizono
authors.affiliation: Department of Digestive Surgery, Breast and Thyroid surgery Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, 890-8520, Japan. hokumura@m.kufm.kagoshima-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okumura
authors.affiliation: Department of Digestive Surgery, Breast and Thyroid surgery Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, 890-8520, Japan. anakajo@m.kufm.kagoshima-u.ac.jp.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nakajo
authors.affiliation: Department of Digestive Surgery, Breast and Thyroid surgery Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, 890-8520, Japan. ykijima@m3.kufm.kagoshima-u.ac.jp.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kijima
authors.affiliation: Department of Digestive Surgery, Breast and Thyroid surgery Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, 890-8520, Japan. kmaemura@hotmail.co.jp.
authors.forename: Kosei
authors.initials: K
authors.lastname: Maemura
authors.affiliation: Department of Digestive Surgery, Breast and Thyroid surgery Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima, 890-8520, Japan. natsugoe@m2.kufm.kagoshima-u.ac.jp.
authors.forename: Shoji
authors.initials: S
authors.lastname: Natsugoe
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D011379:Prognosis; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D016019:Survival Analysis
chemical_list: D000964:Antimetabolites, Antineoplastic; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D005472:Fluorouracil