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The phosphatidic acid phosphatase lipin-1 facilitates inflammation-driven colon carcinogenesis
Clara Meana, … , Jesús Balsinde, María A. Balboa
Clara Meana, … , Jesús Balsinde, María A. Balboa
Published September 20, 2018
Citation Information: JCI Insight. 2018;3(18):e97506. https://doi.org/10.1172/jci.insight.97506.
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Research Article Gastroenterology Inflammation

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

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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.

Authors

Clara Meana, Ginesa García-Rostán, Lucía Peña, Gema Lordén, África Cubero, Antonio Orduña, Balázs Győrffy, Jesús Balsinde, María A. Balboa

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Figure 1

Lipin-1 deficiency decreases tumorigenesis in a murine model of colitis-associated cancer (CAC).

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Lipin-1 deficiency decreases tumorigenesis in a murine model of colitis-...
WT and lipin-1–deficient (fld) animals were treated with AOM/DSS as described in the Methods. (A) Weight change along the protocol is shown. Two separate experiments were done with similar results (n = 13). Data represent the mean ± SEM. (B) Number of polyps in the large intestine per animal at day 80 (n = 13). (C) Percentage of animals with polyps (n = 13). (D) Representative open colons from WT and fld animals after AOM/DSS treatment. (E) Polyps per animal in medial and distal colons (n = 7–8). Data represent the mean ± SEM. (F) Images of representative distal colons after CAC induction. (G) Tumor diameter distribution in WT and fld animals (n = 7–8). *P < 0.05; **P < 0.01 by 2-way ANOVA with Tukey’s post hoc test (A) or Student’s t test (B and E).

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