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 4

Effect of RIP140 on the proliferation of HCT116 human colon cancer cells.

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Effect of RIP140 on the proliferation of HCT116 human colon cancer cells...
(A) Real-time qPCR analysis of HCT116 cells with or without overexpression of RIP140. Data are expressed in AU after normalization to RS9 mRNA levels. Values are the means ± SD; n = 5 independent experiments. RIP140 protein levels were detected by Western blotting and immunofluorescence. Blot lanes were run on the same gel, but were noncontiguous. Original magnification, ×40. (B) Cell index corresponding to the number of HCT-GFP or HCT-RIP viable cells was measured every 24 hours for a total of 72 hours. (C) Percentages of HCT-GFP and HCT-RIP cells in G1 and S phases were determined in ten fields. Values are the means ± SD, normalized to the total number of cells; n = 5 independent experiments. (D) Volumes of HCT-GFP and HCT-RIP cell xenografts were measured at different times after grafting. Values are the means ± SD; n = 12 xenografts per cell line. (E) Representative necrotic areas observed in xenograft sections stained with H&E. Mann-Whitney test. *P < 0.05; **P < 0.001; ***P < 0.001. Original magnification, ×0.5 (left panels) and ×2.5 (right panels).