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

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 15; pp. 6065 - 6073
• Main Authors: PANNEQUIN, Julie, BONNANS, Caroline, DELAUNAY, Nathalie, RYAN, Joanne, BOURGAUX, Jean-François, JOUBERT, Dominique, HOLLANDE, Frédéric
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.08.2009
• Subjects: Animals; Antineoplastic agents; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Basic Helix-Loop-Helix Transcription Factors; Basic Helix-Loop-Helix Transcription Factors - biosynthesis; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; beta Catenin; beta Catenin - biosynthesis; beta Catenin - genetics; beta Catenin - metabolism; Biochemistry, Molecular Biology; Biological and medical sciences; Calcium-Binding Proteins; Calcium-Binding Proteins - biosynthesis; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cancer; Colorectal Neoplasms; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; DNA-Binding Proteins; DNA-Binding Proteins - metabolism; Down-Regulation; Gastrins; Gastrins - deficiency; Gastrins - metabolism; Gastroenterology. Liver. Pancreas. Abdomen; Genomics; Humans; Intercellular Signaling Peptides and Proteins; Intercellular Signaling Peptides and Proteins - biosynthesis; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Jagged-1 Protein; Life Sciences; Medical sciences; Membrane Proteins; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mucin-2; Mucin-2 - biosynthesis; Pharmacology. Drug treatments; Protein Precursors; Protein Precursors - deficiency; Protein Precursors - metabolism; Receptors, Notch; Receptors, Notch - biosynthesis; Receptors, Notch - genetics; Receptors, Notch - metabolism; RNA, Messenger; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Serrate-Jagged Proteins; Signal Transduction; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Transcription Factor 4; Transcription Factors; Transcription Factors - metabolism; Transcription, Genetic; Transfection; Tumors; Up-Regulation; Wnt Proteins; Wnt Proteins - metabolism; Human; Jagged 1 ligand; Notch receptor; Rectal disease; Targeting; Colorectal cancer; Activation; Malignant tumor; Cell signaling; Colonic disease; Signal transduction; Regulation(control); Target; Digestive diseases; Intestinal disease; Tumor cell; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-2409

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 beta-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.