title: Nuclear Notch3 expression is associated with tumor recurrence in patients with stage II and III colorectal cancer.
abstract: BACKGROUND
  The importance of Notch signaling in colorectal cancer (CRC) tumorigenesis has been recently recognized. However, the significance of Notch3 expression and its association with Notch1 expression in CRC is unclear. In the present study, we investigated Notch1 and Notch3 expression in Stage II and III CRC to assess their association with clinicopathological characteristics.
  
  
  METHODS
  The protein expression of Notch1 and Notch3 was examined using immunohistochemistry in 305 CRC specimens. Nuclear expression of Notch1 and Notch3 and their associations with clinicopathological characteristics and distant relapse-free survival (dRFS) were evaluated.
  
  
  RESULTS
  Nuclear Notch1 was overexpressed in 37 % of specimen, and nuclear Notch3 in 38 %. Nuclear Notch3 expression correlated with tumor differentiation status (P = 0.0099). Nuclear expression of Notch1 and Notch3 was associated with tumor recurrence (P = 0.0311 and P = 0.0053, respectively). In multivariate analysis, nuclear Notch3 expression [hazard ratio (HR) = 1.71; 95 % confidence interval (CI), 1.06-2.78; P = 0.0271), lymph node metastasis, and venous involvement were independently correlated with dRFS. In subgroup analysis, nuclear Notch3 expression was strongly associated with dRFS in Stage II CRC (HR = 3.47; 95 % CI 1.44-9.22; P = 0.0055). Both nuclear Notch1 and Notch3 were positive in 67 specimens (22 %) and both were negative in 144 specimens (47 %). Coexpression of nuclear Notch1 and Notch3 had an additive effect toward poorer dRFS compared with a negative subtype (HR = 2.48; 95 % CI, 1.41-4.40; P = 0.0019).
  
  
  CONCLUSIONS
  Nuclear Notch3 expression might be a novel predictive marker for recurrence in Stage II and III CRC.
authors.affiliation: Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, tsu443@hotmail.com.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ozawa
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Kazama
authors.forename: Takashi
authors.initials: T
authors.lastname: Akiyoshi
authors.forename: Koji
authors.initials: K
authors.lastname: Murono
authors.forename: Satomi
authors.initials: S
authors.lastname: Yoneyama
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tanaka
authors.forename: Junichiro
authors.initials: J
authors.lastname: Tanaka
authors.forename: Tomomichi
authors.initials: T
authors.lastname: Kiyomatsu
authors.forename: Kazushige
authors.initials: K
authors.lastname: Kawai
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nozawa
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Kanazawa
authors.forename: Hironori
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Soichiro
authors.initials: S
authors.lastname: Ishihara
authors.forename: Eiji
authors.initials: E
authors.lastname: Sunami
authors.forename: Joji
authors.initials: J
authors.lastname: Kitayama
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D008297:Male; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D051881:Receptor, Notch1 / Q000378:metabolism*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism*; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; C497761:NOTCH1 protein, human; C499374:NOTCH3 protein, human; D051881:Receptor, Notch1; D000071656:Receptor, Notch3; D051880:Receptors, Notch