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
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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 8

RIP140 is a prognosis marker in colon cancer.

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RIP140 is a prognosis marker in colon cancer. (A) Kaplan-Meier plots of ...
(A) Kaplan-Meier plots of cumulative survival of Apc+/+, ApcΔ14/+, and ApcΔ14/+Rip140+/– mice; n = 4 mice for the ApcΔ14/+Rip140+/– genotype and 6 mice for the Apc+/+ and ApcΔ14/+ genotypes. (B) Kaplan-Meier plots of OS of patients with tumors exhibiting low or high RIP140 mRNA expression. (C) RIP140 immunochemistry of a tissue microarray containing adenocarcinomas from fifty-nine patients. Patients were ranked according to RIP140 expression in the tumor and divided into low and high RIP140 expression groups, respectively. Kaplan-Meier plot of the cumulative survival of patients with low or high RIP140 gene expression. A log-rank test was used for statistical analysis. Original magnification, x10. (D) Schematic diagram depicting the role of RIP140 on β-catenin signaling in human colon cancer cells. RIP140 directly increases APC gene expression, which inhibits activation of β-catenin (RIP140 reduces levels of the unphosphorylated form of β-catenin). As a consequence of the drop in ABC levels, RIP140 inhibits Wnt target gene expression and decreases the ability of human colon cancer cells to proliferate and form tumors in nude mice.