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Notch3 signalling promotes tumour growth in colorectal cancer
Author(s) -
Serafin Valentina,
Persano Luca,
Moserle Lidia,
Esposito Giovanni,
Ghisi Margherita,
Curtarello Matteo,
Bonanno Laura,
Masiero Massimo,
Ribatti Domenico,
Stürzl Michael,
Naschberger Elisabeth,
Croner Roland S,
Jubb Adrian M,
Harris Adrian L,
Koeppen Hartmut,
Amadori Alberto,
Indraccolo Stefano
Publication year - 2011
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2895
Subject(s) - notch signaling pathway , cancer research , colorectal cancer , clonogenic assay , biology , cell growth , microbiology and biotechnology , cell , signal transduction , cancer , genetics
Increased Notch1 activity has been observed in intestinal tumours, partially accomplished by β‐catenin‐mediated up‐regulation of the Notch ligand Jagged‐1. Whether further mechanisms of Notch activation exist and other Notch receptors might be involved is unclear. Microarray data indicated that Notch3 transcript levels are significantly up‐regulated in primary and metastatic CRC samples compared to normal mucosa. Moreover, Notch3 protein was expressed at strong/moderate levels by 19.7% of 158 CRC samples analysed, and at weak levels by 51.2% of the samples. Intrigued by these findings, we sought to investigate whether Notch3 modulates oncogenic features of CRC cells. By exploiting xenografts of CRC cells with different tumourigenic properties in mice, we found that the aggressive phenotype was associated with altered expression of components of the Notch pathway, including Notch3, Delta‐like 4 (DLL4), and Jagged‐1 ligands. Stimulation with immobilized recombinant DLL4 or transduction with DLL4‐expressing vectors dramatically increased Notch3 expression in CRC cells, associated with accelerated tumour growth. Forced expression of an active form of Notch3 mirrored the effects of DLL4 stimulation and increased tumour formation. Conversely, attenuation of Notch3 levels by shRNA resulted in perturbation of the cell cycle followed by reduction in cell proliferation, clonogenic capacity, and inhibition of tumour growth. Altogether, these findings indicate that Notch3 can modulate the tumourigenic properties of CRC cells and contributes to sustained Notch activity in DLL4‐expressing tumours. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.