Inhibitor of KappaB Kinase Beta Regulates Gastric Carcinogenesis Via Interleukin-1alpha Expression

Overview

Journal Gastroenterology

Specialty Gastroenterology

Date 2010 Mar 30

PMID 20347815

Citations 36

Authors

Kei Sakamoto

Yohko Hikiba

Hayato Nakagawa

Yoku Hayakawa

Ayako Yanai

Masao Akanuma

Keiji Ogura

Yoshihiro Hirata

Klaus H Kaestner

Masao Omata

Shin Maeda

Affiliations

Soon will be listed here.

Abstract

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.

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