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

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

  • 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

publication date

  • November 2007

has subject area