Colon cancer is a devastating illness that is associated with gut inflammation. Here, we exploredthe possible role of lipin-1, a phosphatidic acid phosphatase, in the development of colitisassociated tumorigenesis. Azoxymethane and dextran sodium sulfate-treated (DSS-treated)animals defcient in lipin-1 harbored fewer tumors and carcinomas than WT animals due todecreased cellular proliferation, lower expression of antiapoptotic and protumorigenic factors, anda reduced infltration of macrophages in colon tumors. They also displayed increased resistance toDSS-induced colitis by producing less proinflammatory cytokines and experiencing less immuneinfltration. Lipin-1-defcient macrophages from the colon were less activated and displayedlower phosphatidic acid phosphatase activity than WT macrophages isolated from DSS-treatedanimals. Transference of WT macrophages into lipin-1-defcient animals was sufcient to increasecolitis burden. Furthermore, treatment of lipin-1-defcient mice with IL-23 exacerbated coloninflammation. Analysis of human databases from colon cancer and ulcerative colitis patientsshowed that lipin-1 expression is increased in those disorders and correlates with the expressionof the proinflammatory markers CXCL1 and CXCL2. And fnally, clinically, LPIN1 expression hadprognostic value in inflammatory and stem-cell subtypes of colon cancers. Collectively, these datademonstrate that lipin-1 is a critical regulator of intestinal inflammation and inflammation-drivencolon cancer development.
ASJC Scopus subject areas