Journal
FASEB JOURNAL
Volume 31, Issue 9, Pages 3816-3830Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201601225RR
Keywords
SMS2; ceramide; colon inflammation; tumorigenesis
Categories
Funding
- Takeda Science Foundation
- Strategic Research Foundation Grant-Aided Project for Private Universities from the Japan Ministry of Education, Culture, Sports, Science, and Technology (MEXT) [S1201004]
- Kanazawa Medical University [H2012-15]
- Grants-in-Aid for Scientific Research [17K18205] Funding Source: KAKEN
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Sphingomyelin synthase 2 (SMS2) is the synthetic enzyme of sphingomyelin (SM), which regulates membrane fluidity and microdomain structure. SMS2 plays a role in LPS-induced lung injury and inflammation; however, its role in inflammation-mediated tumorigenesis is unclear. We investigated the effect of SMS2 deficiency on dextran sodium sulfate (DSS)-induced murine colitis and found inhibition of DSS-induced inflammation in SMS2-deficient (SMS2(-/-)) mice. DSS treatment induced a significant increase in ceramide levels, with a decrease of SM levels in SMS2(-/-) colon tissue, and demonstrated attenuation of the elevation of both inflammation-related gene expression and proinflammatory cytokines and chemokines, leukocyte infiltration, and MAPK and signal transducer and activator of transcription 3 activation. After undergoing transplantation of wild-type bone marrow, SMS2(-/-) mice also exhibited inhibition of DSS-induced inflammation in the colon, which suggested that SMS2 deficiency in bone marrow-derived immune cells was not involved in the inhibition of colitis. Finally, in an azoxymethane/DSS-induced cancer model, SMS2 deficiency significantly decreased tumor incidence in the colon. Our results demonstrate that SMS2 deficiency inhibits DSS-induced colitis and subsequent colitis-associated colon cancer via inhibition of colon epithelial cell-mediated inflammation; therefore, inhibition of SMS2 may be a potential therapeutic target for human colitis and colorectal cancer.
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