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 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Basic Helix-Loop-Helix Transcription Factors / biosynthesis
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Calcium-Binding Proteins / biosynthesis
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism*
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / metabolism*
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Colorectal Neoplasms / pathology
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DNA-Binding Proteins / metabolism
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Down-Regulation
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Gastrins / deficiency
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Gastrins / metabolism*
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Humans
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Intercellular Signaling Peptides and Proteins / biosynthesis
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Jagged-1 Protein
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Membrane Proteins / biosynthesis
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Inbred C57BL
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Mucin-2 / biosynthesis
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Protein Precursors / deficiency
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Protein Precursors / metabolism*
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Receptors, Notch / biosynthesis
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Receptors, Notch / genetics
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Receptors, Notch / metabolism*
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Serrate-Jagged Proteins
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Signal Transduction
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Transcription Factor 4
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Transcription Factors / metabolism
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Transcription, Genetic
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Transfection
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Up-Regulation
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Wnt Proteins / metabolism*
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beta Catenin / biosynthesis
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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ATOH1 protein, human
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Basic Helix-Loop-Helix Transcription Factors
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Calcium-Binding Proteins
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DNA-Binding Proteins
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Gastrins
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Intercellular Signaling Peptides and Proteins
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JAG1 protein, human
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Jag1 protein, mouse
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Jagged-1 Protein
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MUC2 protein, human
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Membrane Proteins
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Mucin-2
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Protein Precursors
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RNA, Messenger
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Receptors, Notch
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Serrate-Jagged Proteins
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TCF4 protein, human
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Transcription Factor 4
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Transcription Factors
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Wnt Proteins
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beta Catenin
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big gastrin