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

Abstract

Background & Aims: Nuclear factor-κB (NF-κB) is an important transcription factor involved in various biological processes, including carcinogenesis. However, it is unknown whether NF-κB activation is involved in gastric carcinogenesis. Methods: To explore the roles of inhibitor of κB kinase (IKKβ), the key kinase for NF-κB activation, in gastric epithelium, we established a conditional gastric mucosal epithelium knockout mouse (IkkβΔST). 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 IkkβΔST and controls (IkkβF/F). The number of tumors was significantly less in the MNU-treated IkkβΔST group than in the IkkβF/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)-1α was up-regulated significantly in control mice compared with IkkβΔST mice, whereas the levels of IL-1β, IL-6, and tumor necrosis factor-α were unchanged. MNU significantly increased apoptotic cell death in IkkβΔST mice compared with IkkβF/F mice, and apoptosis was dependent on decreased IL-1α expression. IL-1α 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: IKKβ regulates gastric carcinogenesis via IL-1α expression, which is associated with anti-apoptotic signaling and cell proliferation. © 2010 AGA Institute.