BACKGROUND & AIMS: Nuclear factor-kappaB (NF-kappaB) is an important transcription factor involved in various biological processes, including carcinogenesis. However, it is unknown whether NF-kappaB activation is involved in gastric carcinogenesis. METHODS: To explore the roles of inhibitor of kappaB kinase (IKKbeta), the key kinase for NF-kappaB activation, in gastric epithelium, we established a conditional gastric mucosal epithelium knockout mouse (Ikkbeta(DeltaST)). Gastric cancer was induced using N-methyl-N-nitrosourea (MNU). After 8 months, the number of tumors and their sizes were evaluated. Apoptosis was analyzed by terminal deoxynucleotidyl transferase-mediated deoxyuridine nick-end labeling staining, and levels of inflammatory cytokines were measured. RESULTS: No phenotypical or histologic difference was observed between untreated Ikkbeta(DeltaST) and controls (Ikkbeta(F/F)). The number of tumors was significantly less in the MNU-treated Ikkbeta(DeltaST) group than in the Ikkbeta(F/F) group (mean +/- standard error, 2.21 +/- 0.48 vs 0.80 +/- 0.23), and the size of the tumors did not differ (2.75 +/- 0.99 vs 2.89 +/- 1.12 mm). After a single oral dose of MNU, interleukin (IL)-1alpha was up-regulated significantly in control mice compared with Ikkbeta(DeltaST) mice, whereas the levels of IL-1beta, IL-6, and tumor necrosis factor-alpha were unchanged. MNU significantly increased apoptotic cell death in Ikkbeta(DeltaST) mice compared with Ikkbeta(F/F) mice, and apoptosis was dependent on decreased IL-1alpha expression. IL-1alpha also induced the proliferation of gastric cancer cells. Fewer tumors were observed in IL-1-receptor knockout mice (Il-1r(-/-); 1.17 +/- 0.44) than in control mice (2.42 +/- 0.52). CONCLUSIONS: IKKbeta regulates gastric carcinogenesis via IL-1alpha expression, which is associated with anti-apoptotic signaling and cell proliferation. Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
BACKGROUND & AIMS: Nuclear factor-kappaB (NF-kappaB) is an important transcription factor involved in various biological processes, including carcinogenesis. However, it is unknown whether NF-kappaB activation is involved in gastric carcinogenesis. METHODS: To explore the roles of inhibitor of kappaB kinase (IKKbeta), the key kinase for NF-kappaB activation, in gastric epithelium, we established a conditional gastric mucosal epithelium knockout mouse (Ikkbeta(DeltaST)). Gastric cancer was induced using N-methyl-N-nitrosourea (MNU). After 8 months, the number of tumors and their sizes were evaluated. Apoptosis was analyzed by terminal deoxynucleotidyl transferase-mediated deoxyuridine nick-end labeling staining, and levels of inflammatory cytokines were measured. RESULTS: No phenotypical or histologic difference was observed between untreated Ikkbeta(DeltaST) and controls (Ikkbeta(F/F)). The number of tumors was significantly less in the MNU-treated Ikkbeta(DeltaST) group than in the Ikkbeta(F/F) group (mean +/- standard error, 2.21 +/- 0.48 vs 0.80 +/- 0.23), and the size of the tumors did not differ (2.75 +/- 0.99 vs 2.89 +/- 1.12 mm). After a single oral dose of MNU, interleukin (IL)-1alpha was up-regulated significantly in control mice compared with Ikkbeta(DeltaST) mice, whereas the levels of IL-1beta, IL-6, and tumor necrosis factor-alpha were unchanged. MNU significantly increased apoptotic cell death in Ikkbeta(DeltaST) mice compared with Ikkbeta(F/F) mice, and apoptosis was dependent on decreased IL-1alpha expression. IL-1alpha also induced the proliferation of gastric cancer cells. Fewer tumors were observed in IL-1-receptor knockout mice (Il-1r(-/-); 1.17 +/- 0.44) than in control mice (2.42 +/- 0.52). CONCLUSIONS:IKKbeta regulates gastric carcinogenesis via IL-1alpha expression, which is associated with anti-apoptotic signaling and cell proliferation. Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
Authors: E M El-Omar; M Carrington; W H Chow; K E McColl; J H Bream; H A Young; J Herrera; J Lissowska; C C Yuan; N Rothman; G Lanyon; M Martin; J F Fraumeni; C S Rabkin Journal: Nature Date: 2000-03-23 Impact factor: 49.962
Authors: S Maeda; H Yoshida; K Ogura; Y Mitsuno; Y Hirata; Y Yamaji; M Akanuma; Y Shiratori; M Omata Journal: Gastroenterology Date: 2000-07 Impact factor: 22.682
Authors: Maya Dajee; Mirella Lazarov; Jennifer Y Zhang; Ti Cai; Cheryl L Green; Alan J Russell; M Peter Marinkovich; Shiying Tao; Qun Lin; Yoshiaki Kubo; Paul A Khavari Journal: Nature Date: 2003-02-06 Impact factor: 49.962
Authors: Florian R Greten; Lars Eckmann; Tim F Greten; Jin Mo Park; Zhi-Wei Li; Laurence J Egan; Martin F Kagnoff; Michael Karin Journal: Cell Date: 2004-08-06 Impact factor: 41.582
Authors: H-M Yun; J H Oh; J-H Shim; J O Ban; K-R Park; J-H Kim; D H Lee; J-W Kang; Y H Park; D Yu; Y Kim; S B Han; D-Y Yoon; J T Hong Journal: Cell Death Dis Date: 2013-05-23 Impact factor: 8.469