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 language | English (US) |
|---|---|
| Pages (from-to) | 1554-1568 |
| Number of pages | 15 |
| Journal | Gastroenterology |
| Volume | 133 |
| Issue number | 5 |
| DOIs | |
| State | Published - Nov 2007 |
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ASJC Scopus subject areas
- Gastroenterology
Cite this
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 journal › Article
}
TY - JOUR
T1 - β-Catenin/Tcf-4 Inhibition After Progastrin Targeting Reduces Growth and Drives Differentiation of Intestinal Tumors
AU - Pannequin, Julie
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
AU - Lambeau, Gérard
AU - Jay, Philippe
AU - Joubert, Dominique
AU - Hollande, Frédéric
PY - 2007/11
Y1 - 2007/11
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=35748959029&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2007.08.023
DO - 10.1053/j.gastro.2007.08.023
M3 - Article
VL - 133
SP - 1554
EP - 1568
JO - Gastroenterology
JF - Gastroenterology
SN - 0016-5085
IS - 5
ER -