β-Catenin/Tcf-4 Inhibition After Progastrin Targeting Reduces Growth and Drives Differentiation of Intestinal Tumors

Julie Pannequin, Nathalie Delaunay, Michael Buchert, Fanny Surrel, Jean François Bourgaux, Joanne Ryan, Stéphanie Boireau, Jessica Coelho, André Pélegrin, Pomila Singh, Arthur Shulkes, Mildred Yim, Graham S. Baldwin, Christine Pignodel, Gérard Lambeau, Philippe Jay, Dominique Joubert, Frédéric Hollande

Research output: Contribution to journalArticle

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Abstract

Background & Aims: Aberrant activation of the β-catenin/Tcf-4 transcriptional complex represents an initiating event for colorectal carcinogenesis, shifting the balance from differentiation toward proliferation in colonic crypts. Here, we assessed whether endogenous progastrin, encoded by a target gene of this complex, was in turn able to regulate β-catenin/Tcf-4 activity in adenomatous polyposis coli (APC)-mutated cells, and we analyzed the impact of topical progastrin depletion on intestinal tumor growth in vivo. Methods: Stable or transient RNA silencing of the GAST gene was induced in human tumor cells and in mice carrying a heterozygous Apc mutation (APCΔ14), which overexpress progastrin but not amidated or glycine-extended gastrin. Results: Depletion of endogenous progastrin production strongly decreased intestinal tumor growth in vivo through a marked inhibition of constitutive β-catenin/Tcf-4 activity in tumor cells. This effect was mediated by the de novo expression of the inhibitor of β-catenin and Tcf-4 (ICAT), resulting from a down-regulation of integrin-linked kinase in progastrin-depleted cells. Accordingly, ICAT down-regulation was correlated with progastrin overexpression and Tcf-4 target gene activation in human colorectal tumors, and ICAT repression was detected in the colon epithelium of tumor-prone, progastrin-overexpressing mice. In APCΔ14 mice, small interfering RNA-mediated progastrin depletion not only reduced intestinal tumor size and numbers, but also increased goblet cell lineage differentiation and cell apoptosis in the remaining adenomas. Conclusions: Thus, depletion of endogenous progastrin inhibits the tumorigenicity of APC-mutated colorectal cancer cells in vivo by promoting ICAT expression, thereby counteracting Tcf-4 activity. Progastrin targeting strategies should provide an exciting prospect for the differentiation therapy of colorectal cancer.

Original languageEnglish (US)
Pages (from-to)1554-1568
Number of pages15
JournalGastroenterology
Volume133
Issue number5
DOIs
StatePublished - Nov 2007

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Catenins
Growth
Neoplasms
Colorectal Neoplasms
Adenomatous Polyposis Coli
Down-Regulation
big gastrin
Goblet Cells
Gastrins
Cell Lineage
RNA Interference
Adenoma
Glycine
Small Interfering RNA
Transcriptional Activation
Genes
Cell Differentiation
Colon
Carcinogenesis
Epithelium

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Pannequin, J., Delaunay, N., Buchert, M., Surrel, F., Bourgaux, J. F., Ryan, J., ... Hollande, F. (2007). β-Catenin/Tcf-4 Inhibition After Progastrin Targeting Reduces Growth and Drives Differentiation of Intestinal Tumors. Gastroenterology, 133(5), 1554-1568. https://doi.org/10.1053/j.gastro.2007.08.023

β-Catenin/Tcf-4 Inhibition After Progastrin Targeting Reduces Growth and Drives Differentiation of Intestinal Tumors. / Pannequin, Julie; Delaunay, Nathalie; Buchert, Michael; Surrel, Fanny; Bourgaux, Jean François; Ryan, Joanne; Boireau, Stéphanie; Coelho, Jessica; Pélegrin, André; Singh, Pomila; Shulkes, Arthur; Yim, Mildred; Baldwin, Graham S.; Pignodel, Christine; Lambeau, Gérard; Jay, Philippe; Joubert, Dominique; Hollande, Frédéric.

In: Gastroenterology, Vol. 133, No. 5, 11.2007, p. 1554-1568.

Research output: Contribution to journalArticle

Pannequin, J, Delaunay, N, Buchert, M, Surrel, F, Bourgaux, JF, Ryan, J, Boireau, S, Coelho, J, Pélegrin, A, Singh, P, Shulkes, A, Yim, M, Baldwin, GS, Pignodel, C, Lambeau, G, Jay, P, Joubert, D & Hollande, F 2007, 'β-Catenin/Tcf-4 Inhibition After Progastrin Targeting Reduces Growth and Drives Differentiation of Intestinal Tumors', Gastroenterology, vol. 133, no. 5, pp. 1554-1568. https://doi.org/10.1053/j.gastro.2007.08.023
Pannequin, Julie ; Delaunay, Nathalie ; Buchert, Michael ; Surrel, Fanny ; Bourgaux, Jean François ; Ryan, Joanne ; Boireau, Stéphanie ; Coelho, Jessica ; Pélegrin, André ; Singh, Pomila ; Shulkes, Arthur ; Yim, Mildred ; Baldwin, Graham S. ; Pignodel, Christine ; Lambeau, Gérard ; Jay, Philippe ; Joubert, Dominique ; Hollande, Frédéric. / β-Catenin/Tcf-4 Inhibition After Progastrin Targeting Reduces Growth and Drives Differentiation of Intestinal Tumors. In: Gastroenterology. 2007 ; Vol. 133, No. 5. pp. 1554-1568.
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AU - Delaunay, Nathalie

AU - Buchert, Michael

AU - Surrel, Fanny

AU - Bourgaux, Jean François

AU - Ryan, Joanne

AU - Boireau, Stéphanie

AU - Coelho, Jessica

AU - Pélegrin, André

AU - Singh, Pomila

AU - Shulkes, Arthur

AU - Yim, Mildred

AU - Baldwin, Graham S.

AU - Pignodel, Christine

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