Notch-2 and the Notch signaling pathway are regulated by Wnt signaling in colorectal cancer
(English)Manuscript (preprint) (Other academic)
Both Notch and Wnt pathways are key regulators of intestinal homeostasis and alterations in these pathways can lead to development of colorectal cancer, where the Apc/β-catenin-genes in the Wnt signaling pathway are frequently mutated, and active Notch signaling contributes to tumorigenesis by keeping the epithelial cells in a proliferative state. These pathways are simultaneously active in proliferative adenoma cells and a crosstalk between them has been indicated.
Using bioinformatics, we identified and screened proximal Notch pathway gene promoters for putative TCF/LEF1 sites, targets for β-catenin. Wild type (wt)-Apc negatively regulates β-catenin and by using semi-quantitative PCR, induction of wt-Apc or β-catenin silencing in HT29 cells, we observed that several genes in the Notch pathway, including Notch-2, were downregulated. Electrophoretic mobility-shift assay (EMSA) confirmed binding of Lef-1 to Notch-2 as well as other Notch pathway gene promoters and luciferase assays showed an increased activity for the LEF1/TCF-site at position -110 in the Notch-2 promoter upon cotransfection of HT29 or HCT116 cells with mutated β-catenin. Taken together, these results indicate that activation of the Wnt pathway with increased levels of β-catenin can function as a transcriptional regulator of the Notch pathway in colon cancer cell lines.
Notch signaling, Notch-2, APC, β-catenin, crosstalk, colorectal cancer
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-51728OAI: oai:DiVA.org:liu-51728DiVA: diva2:277159