| First Author | Iida T | Year | 2020 |
| Journal | Cell Mol Gastroenterol Hepatol | Volume | 9 |
| Issue | 2 | Pages | 277-293 |
| PubMed ID | 31622786 | Mgi Jnum | J:306836 |
| Mgi Id | MGI:6717842 | Doi | 10.1016/j.jcmgh.2019.10.003 |
| Citation | Iida T, et al. (2020) Down-regulation of RalGTPase-Activating Protein Promotes Colitis-Associated Cancer via NLRP3 Inflammasome Activation. Cell Mol Gastroenterol Hepatol 9(2):277-293 |
| abstractText | BACKGROUND & AIMS: Ral guanosine triphosphatase-activating protein alpha2 (RalGAPalpha2) 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. METHODS: We used wild-type (WT) mice and RalGAPalpha2 knockout (KO) mice that showed Ral activation, and bone marrow chimeric mice were generated as follows: WT to WT, WT to RalGAPalpha2 KO, RalGAPalpha2 KO to WT, and RalGAPalpha2 KO to RalGAPalpha2 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. RESULTS: Bone marrow chimeric mice showed that immune cell function between WT mice and RalGAPalpha2 KO mice was not significantly different in the CAC mechanism. RalGAPalpha2 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 RalGAPalpha2 KO mice than in WT mice. The expression levels of interleukin 1beta, NLRP3, apoptosis associated speck-like protein containing a CARD, and caspase-1 were apparently increased in the tumors of RalGAPalpha2 KO mice compared with WT mice. NLRP3 inhibitor reduced the number of invasive tumors. CONCLUSIONS: Ral activation participates in the mechanism of CAC development via NLRP3 inflammasome activation. |
