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Group III phospholipase A 2 promotes colitis and colorectal cancer.

Authors :: Murase R
Taketomi Y
Miki Y
Nishito Y
Saito M
Fukami K
Yamamoto K
Murakami M
Source :: Scientific reports [Sci Rep] 2017 Sep 25; Vol. 7 (1), pp. 12261. Date of Electronic Publication: 2017 Sep 25.
Publication Year :: 2017
Abstract: Lipid mediators play pivotal roles in colorectal cancer and colitis, but only a limited member of the phospholipase A <subscript>2</subscript> (PLA <subscript>2</subscript> ) 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 <subscript>2</subscript> group III (sPLA <subscript>2</subscript> -III) is associated with colorectal cancer, although its precise role remains obscure. Here we have found that sPLA <subscript>2</subscript> -III-null (Pla2g3 <superscript>-/-</superscript> ) mice are highly resistant to colon carcinogenesis. Furthermore, Pla2g3 <superscript>-/-</superscript> mice are less susceptible to dextran sulfate-induced colitis, implying that the amelioration of colonic inflammation by sPLA <subscript>2</subscript> -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 <superscript>-/-</superscript> mice. Overall, our results establish a role of sPLA <subscript>2</subscript> -III in the promotion of colorectal inflammation and cancer, expand our understanding of the divergent roles of multiple PLA <subscript>2</subscript> enzymes in the gastrointestinal tract, and point to sPLA <subscript>2</subscript> -III as a novel druggable target for colorectal diseases.