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Essential requirement for β-arrestin2 in mouse intestinal tumors with elevated Wnt

Caroline Bonnansa,b,c, Maud Flacelièrea,b,c, Fanny Grilleta,b,c, Christelle Danteca,b,c,d, Jean-Pierre Desvignesa,b,c,d, Julie Pannequina,b,c, Dany Severaca,b,c,d, Emeric Duboisa,b,c,d, Frédéric Bibeaue, Virginie Escriouf,g,h, Philippe Crespya,b,c, Laurent Journota,b,c,d, Frédéric Holland a,b,c, and Dominique Jouberta,b,c  
a. Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France 
b. Institut National de la Santé et de la Recherche Médical (INSERM) U661, F-34000 Montpellier, France
c. Universités de Montpellier 1 and 2, UMR 5203, F-34000 Montpellier, France
d. Montpellier GenomiX, c/o Institut de Génomique Fonctionnelle, F-34000 Montpellier, France
e. Department of Pathology, Centre Régional de Lutte Contre le Cancer Val d’Aurelle-Paule Lamarque, Parc Euromédicine, F-34000 Montpellier, France
f. CNRS UMR 8151, INSERM U1022, F-75006 Paris, France
g. Chemical and Genetic Pharmacology and Imaging Laboratory, Faculté de Pharmacie, Université Paris Descartes, F75270 Paris, France
h. Ecole Nationale Supérieure de Chimie de Paris, F-75005 Paris, France

Abstract

β-Arrestins (Arrb) participate in the regulation of multiple signaling pathways, including Wnt/βcatenin, the major actor in human colorectal cancer initiation. To better understand the roles of Arrb in intestinal tumorigenesis, a reverse genetic approach (Arrb−/−) and in vivo siRNA treatment were used in ApcΔ14/+ mice. Mice with Arrb2 depletion (knockout and siRNA) developed only 33% of the tumors detected in their Arrb2-WT littermates, whereas Arrb1 depletion remained without significant effect. These remaining tumors grow normally and are essentially Arrb2–independent. Unsupervised hierarchical clustering analysis showed that they clustered with 25% of Apc∆14/+;Arrb2+/+ tumors. Genes overexpressed in this subset reflect a high interaction with the immune system, whereas those overexpressed in Arrb2–dependent tumors are predominantly involved in Wnt signaling, cell adhesion, migration, and extracellular matrix remodeling. The involvement of Arrb2 in intestinal tumor development via the regulation of the Wnt pathway is supported by ex vivo and in vitro experiments using either tumors from Apc∆14/+ mice or murine ApcMin/+ cells. Indeed, Arrb2 siRNAs decreased the expression of Wnt target genes in cells isolated from 12 of 18 tumors from Apc∆14/+ mice. In ApcMin/+ cells, Arrb2 siRNAs completely reversed the increased Wnt activity and colony formation in soft agar induced by Apc siRNA treatment, whereas they did not affect these parameters in basal conditions or in cells expressing constitutively active βcatenin. We demonstrate that Arrb2 is essential for the initiation and growth of intestinal tumors displaying elevated Wnt pathway activity and identify a previously unsuspected molecular heterogeneity among tumors induced by truncating Apc mutations

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