Group III phospholipase A2 promotes colitis and colorectal cancer

Sci Rep. 2017 Sep 25;7(1):12261. doi: 10.1038/s41598-017-12434-z.

Remi Murase ¹ ², Yoshitaka Taketomi ¹ ², Yoshimi Miki ¹ ², Yasumasa Nishito ³, Moe Saito ² ⁴, Kiyoko Fukami ⁴, Kei Yamamoto ² ⁵ ⁶, Makoto Murakami ⁷ ⁸ ⁹

Affiliations

1 Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
2 Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
3 Core Technology and Research Center, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
4 Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, 192-0392, Tokyo, Japan.
5 Faculty of Bioscience and Bioindustry, Tokushima University, 2-1 Minami-Josanjima, Tokushima, 770-8513, Japan.
6 PRIME, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo, 100-0004, Japan.
7 Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. makmurak@m.u-tokyo.ac.jp.
8 Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan. makmurak@m.u-tokyo.ac.jp.
9 AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo, 100-0004, Japan. makmurak@m.u-tokyo.ac.jp.

PMID: 28947740 DOI: 10.1038/s41598-017-12434-z

Abstract

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 sulfate-induced 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 steady-state 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.

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