Notch3 signalling promotes tumour growth in colorectal cancer.
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 Notc...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2011
|
| _version_ | 1797059731180748800 |
|---|---|
| author | Serafin, V Persano, L Moserle, L Esposito, G Ghisi, M Curtarello, M Bonanno, L Masiero, M Ribatti, D Stürzl, M Naschberger, E Croner, R Jubb, A Harris, A Koeppen, H Amadori, A Indraccolo, S |
| author_facet | Serafin, V Persano, L Moserle, L Esposito, G Ghisi, M Curtarello, M Bonanno, L Masiero, M Ribatti, D Stürzl, M Naschberger, E Croner, R Jubb, A Harris, A Koeppen, H Amadori, A Indraccolo, S |
| author_sort | Serafin, V |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T20:08:23Z |
| format | Journal article |
| id | oxford-uuid:29b0afda-0401-4e82-afea-04f0d0fcd2bc |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:08:23Z |
| publishDate | 2011 |
| record_format | dspace |
| spelling | oxford-uuid:29b0afda-0401-4e82-afea-04f0d0fcd2bc2022-03-26T12:20:41ZNotch3 signalling promotes tumour growth in colorectal cancer.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:29b0afda-0401-4e82-afea-04f0d0fcd2bcEnglishSymplectic Elements at Oxford2011Serafin, VPersano, LMoserle, LEsposito, GGhisi, MCurtarello, MBonanno, LMasiero, MRibatti, DStürzl, MNaschberger, ECroner, RJubb, AHarris, AKoeppen, HAmadori, AIndraccolo, SIncreased 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. |
| spellingShingle | Serafin, V Persano, L Moserle, L Esposito, G Ghisi, M Curtarello, M Bonanno, L Masiero, M Ribatti, D Stürzl, M Naschberger, E Croner, R Jubb, A Harris, A Koeppen, H Amadori, A Indraccolo, S Notch3 signalling promotes tumour growth in colorectal cancer. |
| title | Notch3 signalling promotes tumour growth in colorectal cancer. |
| title_full | Notch3 signalling promotes tumour growth in colorectal cancer. |
| title_fullStr | Notch3 signalling promotes tumour growth in colorectal cancer. |
| title_full_unstemmed | Notch3 signalling promotes tumour growth in colorectal cancer. |
| title_short | Notch3 signalling promotes tumour growth in colorectal cancer. |
| title_sort | notch3 signalling promotes tumour growth in colorectal cancer |
| work_keys_str_mv | AT serafinv notch3signallingpromotestumourgrowthincolorectalcancer AT persanol notch3signallingpromotestumourgrowthincolorectalcancer AT moserlel notch3signallingpromotestumourgrowthincolorectalcancer AT espositog notch3signallingpromotestumourgrowthincolorectalcancer AT ghisim notch3signallingpromotestumourgrowthincolorectalcancer AT curtarellom notch3signallingpromotestumourgrowthincolorectalcancer AT bonannol notch3signallingpromotestumourgrowthincolorectalcancer AT masierom notch3signallingpromotestumourgrowthincolorectalcancer AT ribattid notch3signallingpromotestumourgrowthincolorectalcancer AT sturzlm notch3signallingpromotestumourgrowthincolorectalcancer AT naschbergere notch3signallingpromotestumourgrowthincolorectalcancer AT cronerr notch3signallingpromotestumourgrowthincolorectalcancer AT jubba notch3signallingpromotestumourgrowthincolorectalcancer AT harrisa notch3signallingpromotestumourgrowthincolorectalcancer AT koeppenh notch3signallingpromotestumourgrowthincolorectalcancer AT amadoria notch3signallingpromotestumourgrowthincolorectalcancer AT indraccolos notch3signallingpromotestumourgrowthincolorectalcancer |