Group III phospholipase A2 promotes colitis and colorectal cancer

Lipid mediators play pivotal roles in colorectal cancer and colitis, but only a limited member of the phospholipase A(2) (PLA(2)) 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 PLA(2) group III (sPLA(2)-III) is associated with colorectal cancer, although its precise role remains obscure. Here we have found that sPLA(2)-III-null (Pla2g3(-/-)) mice are highly resistant to colon carcinogenesis. Furthermore, Pla2g3(-/-) mice are less susceptible to dextran sulfate-induced colitis, implying that the amelioration of colonic inflammation by sPLA(2)-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 steady-state elevation of colon-protective fatty acids and their oxygenated metabolites in Pla2g3(-/-) mice. Overall, our results establish a role of sPLA(2)-III in the promotion of colorectal inflammation and cancer, expand our understanding of the divergent roles of multiple PLA(2) enzymes in the gastrointestinal tract, and point to sPLA(2)-III as a novel druggable target for colorectal diseases.