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 5

Regulation of β-catenin activation by RIP140 in HCT116 colon cancer cells.

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Regulation of β-catenin activation by RIP140 in HCT116 colon cancer cell...
(A) Total (left panel) and active (right panel) β-catenin in HCT-GFP and HCT-RIP colon cancer cells (β-catenin immunolabeling in green and nuclear staining in blue). Quantifications are the means ± SD; n = 6 independent experiments for each cell line. Original magnification, ×63. (B) Levels of total and ABC proteins were detected by Western blot analysis using specific antibodies in HCT-GFP and HCT-RIP cells. (C) Expression of β-catenin–regulated genes was measured by real-time qPCR. Values represent fold changes ± SD corrected by 28S mRNA and normalized to HCT-GFP cells; n = 6 independent experiments for each cell line. (D) TOP/FOP experiments were performed by transiently transfecting HCT-GFP and HCT-RIP cells (left panel) or MEF WT and MEF RIPKO cells (right panel) with the pTOPflash or pFOPflash reporter plasmids (200 ng). Cells were treated with or without Wnt3a-conditioned medium. Relative luciferase activity was expressed as the mean ratio of TOP/FOP luciferase activities ± SD; n = 3 independent experiments. Mann-Whitney U test. *P < 0.05; **P < 0.001; ***P < 0.001.