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The phosphatidic acid phosphatase lipin-1 facilitates inflammation-driven colon carcinogenesis

AuthorsMeana, Clara ; García-Rostan, Ginesa ; Peña, Lucía ; Lordén, Gema; Cubero, África; Orduña, Antonio; Győrffy, Balázs; Balsinde, Jesús ; Balboa, María A.
Issue Date2018
PublisherAmerican Society for Clinical Investigation
CitationJCI Insight 3(18): e97506 (2018)
AbstractColon cancer is a devastating illness that is associated with gut inflammation. Here, we explored the possible role of lipin-1, a phosphatidic acid phosphatase, in the development of colitis-associated tumorigenesis. Azoxymethane and dextran sodium sulfate–treated (DSS-treated) animals deficient in lipin-1 harbored fewer tumors and carcinomas than WT animals due to decreased cellular proliferation, lower expression of antiapoptotic and protumorigenic factors, and a reduced infiltration of macrophages in colon tumors. They also displayed increased resistance to DSS-induced colitis by producing less proinflammatory cytokines and experiencing less immune infiltration. Lipin-1–deficient macrophages from the colon were less activated and displayed lower phosphatidic acid phosphatase activity than WT macrophages isolated from DSS-treated animals. Transference of WT macrophages into lipin-1–deficient animals was sufficient to increase colitis burden. Furthermore, treatment of lipin-1–deficient mice with IL-23 exacerbated colon inflammation. Analysis of human databases from colon cancer and ulcerative colitis patients showed that lipin-1 expression is increased in those disorders and correlates with the expression of the proinflammatory markers CXCL1 and CXCL2. And finally, clinically, LPIN1 expression had prognostic value in inflammatory and stem-cell subtypes of colon cancers. Collectively, these data demonstrate that lipin-1 is a critical regulator of intestinal inflammation and inflammation-driven colon cancer development.
Publisher version (URL)https://doi.org/10.1172/jci.insight.97506
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