Effect of group III phospholipase A2 deletion in azoxymethane-induced colon carcinogenesis modeled colon. Mus musculus

Lipid mediators play pivotal roles in colorectal cancer and colitis, but only a limited member of the phospholipase A2 (PLA2) subtypes, which lie upstream of various lipid mediators, have been implicated in the positive or negative regulation of these diseases. Clinical and biochemical evidence suggests that secreted PLA2 group III (sPLA2-III) is associated with colorectal cancer, although its precise role remains obscure. Here we have found that sPLA2-III-null (Pla2g3-/-) mice are highly resistant to colon carcinogenesis. Furthermore, Pla2g3-/- mice are less susceptible to dextran sulfateinduced colitis, implying that the amelioration of colonic inflammation by sPLA2-III ablation may underlie the protective effect against colon cancer. Lipidomics analysis of the colon revealed significant reduction of pro-inflammatory/pro-tumorigenic lysophosholipids as well as unusual elevation of colon-protective fatty acids and their oxygenated metabolites in Pla2g3-/- mice. Overall, our results establish a role of sPLA2-III in the promotion of colorectal inflammation and cancer, expand our understanding of the divergent roles of multiple PLA2 enzymes in the gastrointestinal tract, and point to sPLA2-III as a novel druggable target for colorectal diseases. Overall design: Model, Azoxymethane-induced carcinogenesis. Mice were intraperitoneally administered azoxymethane once a week for 6 weeks and then sacrificed 28 weeks after the last treatment. Condition, tissues with colorectal cancer (AOM) versus normal (vehicle) colon tissues, and Pla2g3 knockout (–/–) versus Pla2g3 wild-type (+/+); Samples, mixed sample of colon tissues from 3-5 mice, respectively