Journal
DIGESTION
Volume 93, Issue 1, Pages 40-46Publisher
KARGER
DOI: 10.1159/000441670
Keywords
Colitis-associated cancer; Inflammatory bowel diseases; Myosin light chain kinase; Tight junction; Tumor necrosis factor
Categories
Funding
- Japanese Ministry of Education, Culture, Sports, Science and Technology
- Japanese Ministry of Health, Labor and Welfare
- Japan Medical Association
- Otsuka Toshimi Scholarship Foundation
- Nihon University Medical Alumni Association
- Abbott Japan Allergy Research Award
- Foundation for Advancement of International Science
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [15K15288] Funding Source: KAKEN
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Prolonged inflammatory bowel diseases (IBD) may lead to colitis-associated carcinogenesis (CAC). Previous studies had shown that nuclear factor-kappa B (NF-kappa B) activation in both macrophages and epithelia in inflamed colonic tissue is associated with CAC development. However, the mechanism by which epithelial NF-kappa B activation leading to CAC development had not previously been rigorously studied. We and others had observed the increased expression of the type 2 receptor for tumor necrosis factor (TNFR2/TNFRSF1b/p75) in IBD models. Myosin light chain kinase (MLCK) is suggested to be associated with epithelial permeability via TNF signaling. Therefore, the relationship between epithelial MLCK expression and NF-kappa B activation via TNFR2 signaling on CAC development was investigated. Pro-tumorigenic cytokines such as interleukin (IL)-1 beta, IL-6 and macrophage inflammatory protein-2 at the lamina propria were increased in the setting of colitis and further increased in tumor tissues with upregulated epithelial TNFR2 and MLCK expressions in an animal model of CAC. The upregulated MLCK expression was also observed in TNF-stimulated colonic epithelial cells in vitro in association with the upregulation of TNFR2 but not TNFR1/TNFRSF1a/p55. Gene silencing of tnfrsf1b, but not tn-frsf1a, resulted in restoration of epithelial tight junction (TJ) associated with decreased MLCK expression. The presence of anti-TNF antibody also resulted in restoration of TJ in association with suppressed MLCK expression, and interestingly, similar results including the suppressed TNFR2 and MLCK expressions were observed by inhibiting MLCK in the epithelial cells. MLCK silencing also led to suppressed TNFR2 expression, suggesting that the restored TJ leads to reduced TNFR2 signaling. Such suppression of MLCK as well as blockade of TNFR2 signaling resulted in reduced CAC development, restored TJ, and decreased pro-tumorigenic cytokines. These imply that TNF-induced NF-kappa B activation and MLCK expression may be a potential target for the prevention of IBD-associated carcinogenesis.
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