1. The phosphatidic acid phosphatase lipin-1 facilitates inflammation-driven colon carcinogenesis.
- Author
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Meana C, García-Rostán G, Peña L, Lordén G, Cubero Á, Orduña A, Győrffy B, Balsinde J, and Balboa MA
- Subjects
- Animals, Azoxymethane therapeutic use, Cell Proliferation, Chemokine CXCL1 metabolism, Chemokine CXCL2 metabolism, Colitis chemically induced, Colitis metabolism, Colitis pathology, Colonic Neoplasms chemically induced, Colonic Neoplasms pathology, Cytokines metabolism, Dextran Sulfate therapeutic use, Disease Models, Animal, Female, Humans, Inflammatory Bowel Diseases metabolism, Interleukin-23 metabolism, Macrophages metabolism, Macrophages pathology, Mice, Mice, Inbred BALB C, Mucous Membrane, Nuclear Proteins adverse effects, Nuclear Proteins genetics, Phosphatidate Phosphatase adverse effects, Phosphatidate Phosphatase genetics, Carcinogenesis metabolism, Colon, Colonic Neoplasms metabolism, Inflammation metabolism, Nuclear Proteins metabolism, Phosphatidate Phosphatase metabolism
- Abstract
Colon 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.
- Published
- 2018
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