title: Myosin light chain kinase expression induced via tumor necrosis factor receptor 2 signaling in the epithelial cells regulates the development of colitis-associated carcinogenesis.
abstract: It has been suggested that prolonged inflammatory bowel diseases (IBD) may lead to colitis-associated carcinogenesis (CAC). We previously observed that the NF-κB activation in colonic epithelial cells is associated with increased tumor necrosis factor receptor 2 (TNFR2) expression in CAC development. However, the mechanism by which epithelial NF-κB activation leading to CAC is still unclear. Myosin light chain kinase (MLCK) has been reported to be responsible for the epithelial permeability associated with TNF signaling. Therefore we focused on the role of MLCK expression via TNFR2 signaling on CAC development. Pro-tumorigenic cytokines such as IL-1β, IL-6 and MIP-2 production as well as INF-γ and TNF production at the lamina propria were increased in the setting of colitis, and further in tumor tissues in associations with up-regulated TNFR2 and MLCK expressions in the epithelial cells of a CAC model. The up-regulated MLCK expression was observed in TNF-stimulated colonic epithelial cells in a dose-dependent fashion in association with up-regulation of TNFR2. Silencing TNFR2, but not TNFR1, resulted in restoration of epithelial tight junction (TJ) associated with decreased MLCK expression. Antibody-mediated blockade of TNF signaling also resulted in restoration of TJ in association with suppressed MLCK expression, and interestingly, similar results were observed with suppressing TNFR2 and MLCK expressions by inhibiting MLCK in the epithelial cells. Silencing of MLCK also resulted in suppressed TNFR2, but not TNFR1, expression, suggesting that the restored TJ leads to reduced TNFR2 signaling. Such suppression of MLCK as well as blockade of TNFR2 signaling resulted in restored TJ, decreased pro-tumorigenic cytokines and reduced CAC development. These results suggest that MLCK may be a potential target for the prevention of IBD-associated tumor development.
authors: Department of Gastroenterology, Graduate School of Medical Science, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Masahiro
authors: M
authors: Suzuki
authors: Department of Gastroenterology, Graduate School of Medical Science, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Takashi
authors: T
authors: Nagaishi
authors: Department of Obstetrics and Gynecology, Nihon University School of Medicine, Tokyo, Japan.
authors: Motomi
authors: M
authors: Yamazaki
authors: Department of Gastroenterology, Graduate School of Medical Science, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Michio
authors: M
authors: Onizawa
authors: Department of Gastroenterology, Graduate School of Medical Science, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Taro
authors: T
authors: Watabe
authors: Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Yuriko
authors: Y
authors: Sakamaki
authors: Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Shizuko
authors: S
authors: Ichinose
authors: Department of Applied Biological Chemistry, The University of Tokyo, Tokyo, Japan.
authors: Mamoru
authors: M
authors: Totsuka
authors: Department of Gastroenterology, Graduate School of Medical Science, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Shigeru
authors: S
authors: Oshima
authors: Department of Gastroenterology, Graduate School of Medical Science, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Ryuichi
authors: R
authors: Okamoto
authors: Department of Chemistry, Tokyo University of Science, Tokyo, Japan.
authors: Motoyuki
authors: M
authors: Shimonaka
authors: Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors: Hideo
authors: H
authors: Yagita
authors: Department of Gastroenterology, Graduate School of Medical Science, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Tetsuya
authors: T
authors: Nakamura
authors: Department of Gastroenterology, Graduate School of Medical Science, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Mamoru
authors: M
authors: Watanabe
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000378:metabolism / Q000473:pathology*; D003106:Colon / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D005260:Female; D007249:Inflammation / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D009219:Myosin-Light-Chain Kinase