Augmented <i>O</i>-GlcNAcylation alleviates inflammation-mediated colon carcinogenesis via suppression of acute inflammation

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  • Hirata Yoshimasa
    Department of Internal Medicine II, Faculty of Medicine, Osaka Medical College
  • Nakagawa Takatoshi
    Department of Pharmacology, Faculty of Medicine, Osaka Medical College
  • Moriwaki Kazumasa
    Department of Pharmacology, Faculty of Medicine, Osaka Medical College
  • Koubayashi Eiko
    Department of Internal Medicine II, Faculty of Medicine, Osaka Medical College
  • Kakimoto Kazuki
    Department of Internal Medicine II, Faculty of Medicine, Osaka Medical College
  • Takeuchi Toshihisa
    Department of Internal Medicine II, Faculty of Medicine, Osaka Medical College
  • Inoue Takuya
    Department of Internal Medicine II, Faculty of Medicine, Osaka Medical College
  • Higuchi Kazuhide
    Department of Internal Medicine II, Faculty of Medicine, Osaka Medical College
  • Asahi Michio
    Department of Pharmacology, Faculty of Medicine, Osaka Medical College

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Abstract

<p>Colon cancer prevalence is high worldwide. O-GlcNAcylation has been associated with tumor growth in various tissues, including the colon; however, its link to carcinogenesis is not fully understood. We investigated the association of O-GlcNAcylation with colon carcinogenesis using a 1,2-dimethylhydrazine/dextran sodium sulfate-induced colon carcinogenesis model in wild type and O-GlcNAc transferase-transgenic (Ogt-Tg) mice. The incidence of colon cancer was significantly lower in Ogt-Tg than in wild type mice. The colonic length was not shortened in Ogt-Tg mice, and NF-κB p65 phosphorylation was strongly suppressed, indicating that reduction of inflammation might be related to the alleviation of colon carcinogenesis. Dextran sodium sulfate-induced acute colitis mice were used to evaluate the effect of O-GlcNAcylation on inflammation at the maximal inflammation period. In Ogt-Tg mice, NF-κB p65 phosphorylation and interleukin-1β mRNA expression were suppressed. Histochemical staining demonstrated shedding of colon epithelial cells in wild type mice a few days after dextran sodium sulfate treatment, whereas they remained essentially intact in Ogt-Tg mice. There were no significant differences on histochemical staining in the remaining epithelia between groups. These data suggest that O-GlcNAcylation could prevent colon carcinogenesis through reducing acute maximum inflammation, suggesting modulation of O-GlcNAcylation as a novel therapeutic option.</p>

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