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Cited by 49Wnt/β-catenin signaling in development and cancerReceptor Mechanisms and SignalingColorectal Cancer Treatments and Studies

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

Open access
Bonnans, Caroline, Flacelière, Maud, Grillet, Fanny, Dantec, Christelle, Desvignes, Jean-Pierre, Pannequin, Julie, Severac, Dany, Dubois, Emeric, Bibeau, Frédéric, Escriou, Virginie, Crespy, Philippe, Journot, Laurent, Hollande, Frédéric, Joubert, Dominique·2012·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1109457109PMC PMC3286958
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Abstract

β-Arrestins (Arrb) participate in the regulation of multiple signaling pathways, including Wnt/β-catenin, 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 Apc Δ14/+ 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 Δ14/+ ;Arrb 2 +/+ 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 Δ14/+ mice or murine Apc Min/+ cells. Indeed, Arrb2 siRNAs decreased the expression of Wnt target genes in cells isolated from 12 of 18 tumors from Apc Δ14/+ mice. In Apc Min/+ 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 β-catenin. 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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  • Five activating alterations in Wnt-TGFβ-class (FZD7, FZD6, TCF4, FRAT2 and ARBB2) have been related to Wnt activation in cancer.

    “among which five of them (FZD7, FZD6, TCF4, FRAT2 and ARBB2) have been related to Wnt activation in cancer (20-25)”

    From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [23]

    The Results report that Arrb2 knockdown reduced Wnt/β-catenin activity in a human colorectal cancer cell line with elevated Wnt signaling, supporting a link between ARRB2 and Wnt activity in cancer. The paper does not identify an activating alteration in ARRB2; it attributes the elevated signaling in those cells to APC inactivation. It also does not establish the claim for the other four listed genes. (LLM, conf=0.86)

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  • Several genes dysregulated in Wnt-TGFβ-class characterize Wnt-signaling activation in cancer.

    “In contrast, several genes dysregulated in Wnt-TGFβ-class characterize Wnt-signaling activation in cancer (20-25) (Fig. 6).”

    From Wnt-Pathway Activation in Two Molecular Classes of Hepatocellular Carcinoma and Experimental Modulation by Sorafenib (2012) · cites this paper as [23]

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Research works printed but not linked: 35

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Metadata

Authors
Bonnans, C., Flacelière, M., Grillet, F., Dantec, C., Desvignes, J.-P., Pannequin, J., Severac, D., Dubois, E., Bibeau, F., Escriou, V., Crespy, P., Journot, L., Hollande, F., & Joubert, D.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France;
  • Department of Pathology, Centre Régional de Lutte Contre le Cancer Val d'Aurelle-Paul Lamarque, Parc Euromédecine, F-34000 Montpellier, France;
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2012-02-06
Volume
109
Issue
8
Pages
3047-3052
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1109457109
PMC
PMC3286958
OpenAlex
W1978945918
Cited by
49
References
0
Citations by year
2025: 3 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 5 · 2020: 2 · 2019: 6 · 2018: 6 · 2017: 4 · 2016: 2 · 2015: 6 · 2014: 1 · 2013: 4 · 2012: 5
FWCI
2.06
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Keywords
β-arrestin2, β-arrestin1, Wnt/β-catenin signaling, colorectal cancer, intestinal tumorigenesis, APC mutation, tumor heterogeneity, Wnt target genes, antitumor immunity, extracellular matrix remodeling, cell adhesion, cell migration, soft agar colony formation
MeSH terms
beta-Arrestins, beta-Arrestin 1, beta-Arrestin 2, Transcription Factor 4, Animals, Cell Separation, Cell Transformation, Neoplastic, Humans, Intestinal Neoplasms, Mice, Inbred C57BL, Tumor Stem Cell Assay, Down-Regulation, Gene Expression Regulation, Neoplastic, Arrestins, Adenomatous Polyposis Coli Protein, Cell Proliferation, Mice, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Gene Knockdown Techniques, Wnt Signaling Pathway

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