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 7

RIP140 expression in human colon cancers.

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RIP140 expression in human colon cancers. (A) RIP140 mRNA was quantified...
(A) RIP140 mRNA was quantified in seventeen normal tissues and twenty-two colorectal adenocarcinomas as previously described. Data are presented as box plots showing the median value, upper and lower quartiles, and minimum and maximum nonatypical values. (B) RIP140 mRNA levels expressed in AU after normalization to actin mRNA levels in twenty-four matched normal and tumor colon samples (the means of the two populations are indicated as horizontal lines). (C) RIP140 immunochemistry of a tissue microarray containing normal mucosa from twenty-four patients together with the corresponding adenocarcinoma. Nuclear RIP140–positive cells were counted and are represented in a dot plot. A Mann-Whitney U test was used for statistical analysis. Original magnification, x10. (D) Correlation between RIP140 and APC, MYC, or GAST gene expression in 396 colorectal adenocarcinomas. Statistical significance was assessed using Spearman’s correlation analysis.