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Down-regulation of RalGTPase-Activating Protein Promotes Colitis-Associated Cancer via NLRP3 Inflammasome Activation.

  • Iida, Tomoya1
  • Hirayama, Daisuke1
  • Minami, Naoki2
  • Matsuura, Minoru2
  • Wagatsuma, Kohei1
  • Kawakami, Kentaro1
  • Nagaishi, Kanna3
  • Nojima, Masanori4
  • Ikeuchi, Hiroki5
  • Hirota, Seiichi6
  • Shirakawa, Ryutaro7
  • Horiuchi, Hisanori7
  • Nakase, Hiroshi8
  • 1 Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan. , (Japan)
  • 2 Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan. , (Japan)
  • 3 Second Department of Anatomy, Sapporo Medical University School of Medicine, Sapporo, Japan. , (Japan)
  • 4 Center for Translational Research, The Institute of Medical Science Hospital, The University of Tokyo, Tokyo, Japan. , (Japan)
  • 5 Division of Lower Gastrointestinal, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan; Inflammatory Bowel Disease Center, Hyogo College of Medicine, Nishinomiya, Japan. , (Japan)
  • 6 Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan. , (Japan)
  • 7 Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan. , (Japan)
  • 8 Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan. Electronic address: [email protected] , (Japan)
Published Article
Cellular and Molecular Gastroenterology and Hepatology
Publication Date
Jan 01, 2020
DOI: 10.1016/j.jcmgh.2019.10.003
PMID: 31622786


Ral guanosine triphosphatase-activating protein α2 (RalGAPα2) is the major catalytic subunit of the negative regulators of the small guanosine triphosphatase Ral, a member of the Ras subfamily. Ral regulates tumorigenesis and invasion/metastasis of some cancers; however, the role of Ral in colitis-associated cancer (CAC) has not been investigated. We aimed to elucidate the role of Ral in the mechanism of CAC. We used wild-type (WT) mice and RalGAPα2 knockout (KO) mice that showed Ral activation, and bone marrow chimeric mice were generated as follows: WT to WT, WT to RalGAPα2 KO, RalGAPα2 KO to WT, and RalGAPα2 KO to RalGAPα2 KO mice. CAC was induced in these mice by intraperitoneal injection of azoxymethane followed by dextran sulfate sodium intake. Intestinal epithelial cells were isolated from colon tissues, and we performed complementary DNA microarray analysis. Cytokine expression in normal colon tissues and CAC was analyzed by quantitative polymerase chain reaction. Bone marrow chimeric mice showed that immune cell function between WT mice and RalGAPα2 KO mice was not significantly different in the CAC mechanism. RalGAPα2 KO mice had a significantly larger tumor number and size and a significantly higher proportion of tumors invading the submucosa than WT mice. Higher expression levels of matrix metalloproteinase-9 and matrix metalloproteinase-13 were observed in RalGAPα2 KO mice than in WT mice. The expression levels of interleukin 1β, NLRP3, apoptosis associated speck-like protein containing a CARD, and caspase-1 were apparently increased in the tumors of RalGAPα2 KO mice compared with WT mice. NLRP3 inhibitor reduced the number of invasive tumors. Ral activation participates in the mechanism of CAC development via NLRP3 inflammasome activation. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

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