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The Wnt Target Jagged-1 Mediates the Activation of Notch Signaling by Progastrin in Human Colorectal Cancer Cells

¹ Centre National de la Recherche Scientifique (CNRS) UMR5203; Institut National de la Sante et de la Recherche Medicale (INSERM) U661; University of Montpellier I; University of Montpellier II; Institut de Génomique Fonctionnelle; ² INSERM U888; University of Montpellier 1, Montpellier, France and ³ Service d'Hépato Gastroentérologie, CHU Nimes, Nimes, France

Requests for reprints: Frédéric Hollande, Insitute of Functional Genomics, Centre National de la Recherche Scientifique UMR5203, Institut National de la Sante et de la Recherche Medicale U661, 141 rue de la Cardonille, 34094 Montpellier, France. Phone: 33-467-66-81-44; Fax: 33-467-66-81-49; E-mail: fhollande{at}univ-montp1.fr.

Key Words: progastrin • colorectal carcinoma • Notch • Wnt • Jagged-1

The Wnt and Notch signaling pathways are both abnormally activated in colorectal cancer (CRC). We recently showed that progastrin depletion inhibited Wnt signaling and increased goblet cell differentiation of CRC cells. Here, we show that progastrin down-regulation restores the expression by CRC cells of the early secretory lineage marker Math-1/Hath-1 due to an inhibition of Notch signaling. This effect is mediated by a decreased transcription of the Notch ligand Jagged-1, downstream of β-catenin/Tcf-4. Accordingly, recombinant progastrin sequentially activated the transcription of Wnt and Notch target genes in progastrin-depleted cells. In addition, restoration of Jagged-1 levels in these cells is sufficient to activate Tcf-4 activity, demonstrating the occurrence of a feedback regulation from Notch toward Wnt signaling. These results suggest that progastrin could be instrumental in maintaining the concomitant activation of Wnt and Notch pathways in CRC cells, further highlighting the interest of progastrin targeting for the clinical management of CRC. [Cancer Res 2009;69(15):6065–73]