Inhibitor of kappaB kinase beta regulates gastric carcinogenesis via interleukin-1alpha expression.

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.