Downregulation of RalGTPase-activating protein promotes colitis-associated cancer via NLRP3 inflammasome activation
2019
Abstract Background and Aims RalGTPase-activating protein α2 (RalGAPα2) is the major catalytic subunit of the negative regulators of the small GTPase Ral, a member of 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 RalGAPα2 knockout (KO) mice that exhibited 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 cDNA 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 RalGAPα2 KO mice was not significantly different in 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 (MMP)-9 and MMP-13 were observed in RalGAPα2 KO mice than in WT mice. The expression levels of IL-1β, NLRP3, ASC, and Caspase-1 were apparently elevated in the tumors of RalGAPα2 KO mice compared to WT mice. NLRP3 inhibitor reduced the number of invasive tumors. Conclusions Ral activation participates in the mechanism of CAC development via NLRP3 inflammasome activation.
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