RIP140 increases APC expression and controls intestinal homeostasis and tumorigenesis
Marion Lapierre, … , Malcolm Parker, Vincent Cavailles
Marion Lapierre, … , Malcolm Parker, Vincent Cavailles
Published March 25, 2014
Citation Information: J Clin Invest. 2014;124(5):1899-1913. https://doi.org/10.1172/JCI65178.
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Research Article Oncology

RIP140 increases APC expression and controls intestinal homeostasis and tumorigenesis

Abstract

Deregulation of the Wnt/APC/β-catenin signaling pathway is an important consequence of tumor suppressor APC dysfunction. Genetic and molecular data have established that disruption of this pathway contributes to the development of colorectal cancer. Here, we demonstrate that the transcriptional coregulator RIP140 regulates intestinal homeostasis and tumorigenesis. Using Rip140-null mice and mice overexpressing human RIP140, we found that RIP140 inhibited intestinal epithelial cell proliferation and apoptosis. Interestingly, following whole-body irradiation, mice lacking RIP140 exhibited improved regenerative capacity in the intestine, while mice overexpressing RIP140 displayed reduced recovery. Enhanced RIP140 expression strongly repressed human colon cancer cell proliferation in vitro and after grafting onto nude mice. Moreover, in murine tissues and human cancer cells, RIP140 stimulated APC transcription and inhibited β-catenin activation and target gene expression. Finally, RIP140 mRNA and RIP140 protein levels were decreased in human colon cancers compared with those in normal mucosal tissue, and low levels of RIP140 expression in adenocarcinomas from patients correlated with poor prognosis. Together, these results support a tumor suppressor role for RIP140 in colon cancer.

Authors

Marion Lapierre, Sandrine Bonnet, Caroline Bascoul-Mollevi, Imade Ait-Arsa, Stéphan Jalaguier, Maguy Del Rio, Michela Plateroti, Paul Roepman, Marc Ychou, Julie Pannequin, Frédéric Hollande, Malcolm Parker, Vincent Cavailles

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Figure 1

RIP140 expression in mouse intestinal epithelium.

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RIP140 expression in mouse intestinal epithelium. (A) Immunofluorescence...
(A) Immunofluorescence showing a gradient of RIP140 in the nuclei of epithelial cells along the villus/crypt axis of wild-type mice. Original magnification, ×20. (B) Real-time qPCR analysis of Rip140 mRNA in wild-type intestinal epithelial fractions. mRNAs encoded by the Lyz and Muc2 genes were used to verify the enrichment in villus- or crypt-associated cells. Data were normalized to RS9 mRNA. mRNA quantification for each gene is indicated in AU as the mean ± SD; n = 4 mice. (C) Left panel: H&E-stained transverse sections of small intestine from RIPKO, wild-type, and RIPTg mice. Right panel: The length of villi and crypts was measured on at least six fields selected from whole intestine sections of each mouse of the three different genotypes. Values represent the means ± SD; n = 6 mice for each genotype. Original magnification, ×10. Mann-Whitney U test. **P < 0.01; ***P < 0.001.