The Wnt target jagged-1 mediates the activation of notch signaling by progastrin in human colorectal cancer cells

Julie Pannequin, Caroline Bonnans, Nathalie Delaunay, Joanne Ryan, Jean François Bourgaux, Dominique Joubert, Frédéric Hollande

Research output: Contribution to journalArticleResearchpeer-review

51 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)6065-6073
Number of pages9
JournalCancer Research
Volume69
Issue number15
DOIs
Publication statusPublished - 1 Aug 2009
Externally publishedYes

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