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

Abstract

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.

• Authors: 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
• Journal: Gastroenterology (Gastroenterology) Vol. 133 Issue 5 Pg. 1554-68 (Nov 2007) ISSN: 1528-0012 [Electronic] United States
• PMID: 17920061 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Cell Cycle Proteins
• Ctnnbip1 protein, mouse
• Gastrins
• Protein Precursors
• RNA, Small Interfering
• Repressor Proteins
• TCF Transcription Factors
• TCF7L2 protein, human
• Tcf7l2 protein, mouse
• Transcription Factor 7-Like 2 Protein
• Transcription Factors
• beta Catenin
• big gastrin

Topics

• Adaptor Proteins, Signal Transducing
• Adenoma (genetics, metabolism, pathology)
• Adenomatous Polyposis Coli (genetics)
• Animals
• Apoptosis (physiology)
• Cell Cycle Proteins (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Cell Transformation, Neoplastic (genetics)
• Colorectal Neoplasms (genetics, metabolism, pathology)
• Gastrins (metabolism)
• Gene Expression Regulation, Neoplastic
• Genes, APC
• Humans
• Mice
• Mice, Nude
• Phosphatidylinositol 3-Kinases (physiology)
• Protein Precursors (metabolism)
• RNA, Small Interfering (pharmacology)
• Random Allocation
• Repressor Proteins
• Signal Transduction (physiology)
• TCF Transcription Factors (metabolism)
• Transcription Factor 7-Like 2 Protein
• Transcription Factors (genetics, metabolism)
• Transcriptional Activation
• Transplantation, Heterologous
• beta Catenin (metabolism)