Beta-catenin/Tcf-4 inhibition after progastrin targeting reduces growth and drives differentiation of intestinal tumors.

Beta-catenin/Tcf-4 inhibition after progastrin targeting reduces growth and drives differentiation of intestinal tumors. Research Abstract Details 

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Beta-catenin/Tcf-4 inhibition after progastrin targeting reduces growth and drives differentiation of intestinal tumors. Abstract Text:

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

BACKGROUND & AIMS: Aberrant activation of the beta-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 beta-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 (APCDelta14), 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 beta-catenin/Tcf-4 activity in tumor cells. This effect was mediated by the de novo expression of the inhibitor of beta-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 APCDelta14 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.

Beta-catenin/Tcf-4 inhibition after progastrin targeting reduces growth and drives differentiation of intestinal tumors. Publishing Authors By Initials

J Pannequin,N Delaunay,M Buchert,F Surrel,JF Bourgaux,J Ryan,S Boireau,J Coelho,A ,P Singh,A Shulkes,M Yim,GS Baldwin,C Pignodel,G Lambeau,P Jay,D Joubert,F Hollande,J Pannequin,N Delaunay,M Buchert,F Surrel,JF Bourgaux,J Ryan,S Boireau,J Coelho,A ,P Singh,A Shulkes,M Yim,GS Baldwin,C Pignodel,G Lambeau,P Jay,D Joubert,F Hollande,

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Beta-catenin/Tcf-4 inhibition after progastrin targeting reduces growth and drives differentiation of intestinal tumors. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Gastroenterology

VOLUME: 133

Page Numbers: 1554-68

Journal Abbreviation: Gastroenterology

ISSN: 1528-0012

DAY: 24

MONTH: 10

YEAR: 2007

Beta-catenin/Tcf-4 inhibition after progastrin targeting reduces growth and drives differentiation of intestinal tumors. Information

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LANGUAGE: eng

NlmUniqueID: 374630

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Grant and Affiliation Information for Beta-catenin/Tcf-4 inhibition after progastrin targeting reduces growth and drives differentiation of intestinal tumors.

AFFILIATION: CNRS UMR5203, Montpellier, France.

Country: United States

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MEDLINETA: Gastroenterology

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