Notch3 signalling promotes tumour growth in colorectal cancer

Abstract

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.

Jagged 2 silencing inhibits motility and invasiveness of colorectal cancer cell lines

“…Previous studies have indicated that Notch signaling is upregulated in CRC (15)(16)(17)(18). However, data regarding the expression of JAG2 protein in CRC tissues is scarce.…”

Notch signaling molecules as prognostic biomarkers for non-small cell lung cancer

“…The activation of Notch 1 signaling appears to sustain the motility, migration and invasion of tumor cells in esophagus squamous cell carcinomas, lingual squamous cell carcinoma, endometrial carcinoma and breast cancer (11)(12)(13)(14)(15). Almost all cases of T cell acute lymphoblastic leukemia (T-ALL), and colorectal, pancreatic and ovarian cancer have been reported to exhibit aberrant Notch 3 expression (6,8,16,17). Our previous study also reported that Notch 3 overexpression was associated with a poor prognosis in NSCLC patients (18).…”

Colon cancer progression is driven by APEX1-mediated upregulation of Jagged

“…Using ontology analysis consisting of proliferation, migration, and angiogenesis, we discovered 4 genes that satisfied these 3 biological criteria ( Figure 3, A and B). Among these, JAG1 (which encodes the Notch ligand) was particularly interesting, because activation of Notch signaling is involved in human colon cancer (5,12,13,(33)(34)(35). We also conducted expression microarray profiling of control and GM00637-APEX1 cells.…”

“…Given the importance of Jagged1/Notch signaling in colon carcinogenesis (5,12,34,35,38), the involvement of Jagged1 in APEX1-mediated increased tumorigenicity of colon cancer cells was of interest. Additionally, the transcriptional regulation of human Jagged1 has been elusive.…”