Inhibitor of κB Kinase Beta Regulates Gastric Carcinogenesis via Interleukin-1α Expression

BACKGROUND & AIMS: Nuclear factor-kappa B (NF-kappa B) is an important transcription factor involved in various biological processes, including carcinogenesis. However, it is unknown whether NF-kappa B activation is involved in gastric carcinogenesis. METHODS: To explore the roles of inhibitor of kappa B kinase (IKK beta), the key kinase for NF-kappa B activation, in gastric epithelium, we established a conditional gastric mucosal epithelium knockout mouse (Ikk beta(Delta ST)). 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 Ikk beta(Delta ST) and controls (Ikk beta(F/F)). The number of tumors was significantly less in the MNU-treated Ikk beta(Delta ST) group than in the Ikk beta(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)-1 alpha was up-regulated significantly in control mice compared with Ikk beta(Delta ST) mice, whereas the levels of IL-1 alpha, IL-6, and tumor necrosis factor-alpha were unchanged. MNU significantly increased apoptotic cell death in Ikk beta(Delta ST) mice compared with Ikk beta(F/F) mice, and apoptosis was dependent on decreased IL-1 alpha expression. IL-1 alpha 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: IKK beta regulates gastric carcinogenesis via IL-1 alpha expression, which is associated with anti-apoptotic signaling and cell proliferation.