RIP140 increases APC expression and controls intestinal homeostasis and tumorigenesis
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
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
View: Text | PDF
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

×

Figure 3

Activation of β-catenin by RIP140 in mouse intestinal epithelium.

Options: View larger image (or click on image) Download as PowerPoint
Activation of β-catenin by RIP140 in mouse intestinal epithelium. (A) To...
(A) Total (left panel) and active (right panel) β-catenin (ABC) in paraffin-embedded sections of small intestine from RIPKO, wild-type, and RIPTg mice (β-catenin immunolabeling in green and nuclear staining in blue). Values are the means ± SD; n = 6 mice for each genotype. Original magnification, ×40 (left panels) and ×63 (right panels). (B) Expression of β-catenin–regulated genes was measured by real-time qPCR analysis in RIPKO, wild-type, and RIPTg mice. Values represent fold change ± SD versus levels in wild-type mice after normalization to RS9 mRNA; n = 4 mice for each genotype. (C) Same as in B for the expression of different members of the degradation complex. Mann-Whitney U test. *P < 0.05; **P < 0.001; ***P < 0.001.