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

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 3

Lipin-1 is expressed in tumor macrophages.

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Lipin-1 is expressed in tumor macrophages. (A) Homogenates from white ad...
(A) Homogenates from white adipose tissue (WAT) or normal colon tissue from WT animals were analyzed by immunoblot using specific antibodies against lipin-1 or β-actin as indicated. (B) Tumor contiguous sections from WT animals were stained with H&E (a) or stained by immunohistochemistry using specific antibodies against lipin-1 (b–e). Image panels show: (b) tumor epithelial cells, (c) normal epithelial cells, (d) tumor-infiltrating lymphocytes, (e) tumor stromal cells, and (f) liver (positive staining control for lipin-1). Original magnification, ×10 (a) and ×60 (b–f). (C) Homogenates from WAT, or isolated epithelial cells and macrophages from WT animal tumors were analyzed by immunoblot using specific antibodies against lipin-1 or GAPDH as indicated. (D) Tumor contiguous sections of the same tumor shown in B were stained by immunohistochemistry using antibodies against CD3e (T cells), CD45R (B cells), and lipin-1, as indicated. Original magnification, ×10 and ×60 for magnified insets (right). (E) Colon and tumor sections from WT and lipin-1–deficient (fld) animals were stained by IHC using antibodies against lipin-1. Normal epithelial cells and tumoral epithelial cells are shown. Original magnification, ×60. (F) Contiguous tumor sections from WT and fld animals were stained by IHC using antibodies against F4/80 (macrophages) or CD3e (T cells). Original magnification, ×10. (G) Tumor F4/80+ and CD3e+ infiltrated cells were quantified from tumor sections stained as in F and data are shown as percentage of positive cells with respect to total cells. Cells were counted in 3 different fields per tumor (n = 6 for WT and 5 for fld). ***P < 0.001 by Student’s t test.