Suppressing colon cancer

The prognosis of patients with colorectal cancer depends on the stage of disease at diagnosis and the underlying tumorigenic mutations. The gene encoding the tumor suppressor adenomatous polyposis coli (APC) is commonly mutated in colorectal cancers and results in deregulation of the Wnt/β-catenin pathway. Marion Lapierre and colleagues at the Montpellier Cancer Research Institute identified transcriptional cofactor RIP140 as a positive regulator of APC and genes encoding members of the β-catenin degradation complex. Expression of human RIP140 in mouse intestinal villi reduced intestinal epithelial cell turnover, while RIP140 overexpression in human colon cancer cells blocked cell proliferation in vitro and reduced tumor growth in a murine xenograft model. RIP140 directly activated APC transcription, leading to enhanced APC expression and inhibition of the proto-oncogenic Wnt pathway. In a mouse model of colon cancer, mutations in both Apc and Rip140 dramatically reduced survival compared to animals with only an Apc mutation. Furthermore, RIP140 expression in human colorectal tumor biopsies correlated with APC expression and longer survival, suggesting RIP140 has potential as a prognostic indicator for colon cancer. The accompanying image reveals varying levels of RIP140 (dark purple) in adenocarinomas isolated from colon cancer patients.  Patients with low levels (top row) of RIP140 in tumors had lower survival rates compared to patients with higher levels (bottom row) of RIP140.   

Published March 25, 2014, by Amanda Keener

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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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