RalGAPα2 and NLRP3 Orchestrate Tumor Invasion in Colitis-Associated Cancers

Abstract

hronic inflammation facilitates cancer development, and more invasive phenotypes compared with their sibling Cas illustrated by the increased incidence of colitisassociated cancers (CAC) in patients with inflammatory bowel diseases. CAC have a greater malignant potential than sporadic colorectal cancer, because they are frequently diagnosed at an advanced stage with locally advanced or metastatic disease. Molecular mechanisms involved in CAC development also differ from those in sporadic colorectal cancer, reflecting the prominent role of inflammation-induced carcinogenesis in the development of CAC. How inflammation favors and what are the signaling nodes linking inflammatory and oncogenic pathways are still being uncovered, with the important clinical endpoint to identify therapeutic targets. However, the molecular mechanisms responsible for the acquisition of metastatic ability have not been fully identified. This issue of Cellular and Molecular Gastroenterology and Hepatology features an original article by Iida et al that sheds light on the molecular events underlying CAC development. They show that down-regulation of the RalGAPa2 subunit, the major inhibitory regulator of the small guanosine triphosphatase Ral in the colon, is a key factor driving the invasive tumorigenesis of CAC with up-regulation of matrix metalloproteinase (MMP)-9 and MMP-13 and reveal that it occurs via induction of the NLRP3-IL1b pathway. The oncogenic effects of Ral, amember of the Ras subfamily, have been known for 2 decades, expanding investigations into the role of Ral in controlling multiple cellular functions. Ral regulates tumorigenesis and cancer progression in different ways: through activation of Ral effector proteins, via activation of several signaling pathways, and by phosphorylation of Ral proteins. Ral activation was reported in several human cancers, including bladder, colon, and pancreas cancers, and involved in cell proliferation, migration, and metastasis. This protein is activated by Ral guanine nucleotide exchange factors and inactivated by Ral–guanosine triphosphatase activating proteins (RalGAPs), the latter of which consist of heterodimers containing a catalytic a1 or a2 subunit and a common b subunit. Tumors harboring the down-regulated a2 subunit of the RalGAPs appeared to be more prone to invasion or metastasis. Iida et al reveal that invasive human CAC tumors at more advanced stage display decreased RalGAPa2 expression compared with matching normal tissue and that this might be the cause of aberrant Ral activation. Of note, the expression of RalGAPa2 in CAC was significantly lower than that in sporadic colorectal cancer, suggesting that the mechanisms of Ral activation might be different in the 2 clinical settings. What the host and environmental cues are that determine “low” RalGAPa2 expression profile in CAC remain to be investigated. Consistent with their findings in humans, Iida et al demonstrate that in the AOM/DSS model, RalGAP2 KO mice exhibited significantly larger CAC sizes