Unravelling disparate roles of NOTCH in bladder cancer

Abstract

The Notch pathway has been implicated in both oncogenic and tumour-suppressive roles in cancer depending on the tissue type and cellular context. However, until recently, little was known about the pathway in bladder cancer. Studies have revealed that NOTCH1 copy number and expression are decreased in bladder cancer and NOTCH1 activation in bladder cancer cell lines reduces proliferation, suggesting that NOTCH1 acts as a tumour suppressor. Furthermore, in transgenic models, bladder cancer is promoted by bladder-specific inactivation of a component of the γ-secretase complex, which liberates the intracellular domain of neurogenic locus Notch homologue protein (NOTCH) and starts the signalling cascade. By contrast, further work has demonstrated that NOTCH2 acts as an oncogene that promotes cell proliferation and metastasis through epithelial-to-mesenchymal transition, cell cycle progression, and maintenance of stemness. Studies indicating that NOTCH1 and NOTCH2 have opposite effects on the progression of bladder cancer could give rise to potential therapeutic approaches aimed at blocking or restoring the Notch pathway.

Emerging Roles of Cancer Stem Cells in Bladder Cancer Progression, Tumorigenesis, and Resistance to Chemotherapy: A Potential Therapeutic Target for Bladder Cancer

“…The Notch signaling pathway has both oncogenic and tumor-suppressive effects depending on the organ and cellular context [86]. It involves four receptors (Notch1-4) and five ligands and regulates the transcription of multiple target genes [21].…”

“…It involves four receptors (Notch1-4) and five ligands and regulates the transcription of multiple target genes [21]. The expression of the Notch1 receptor is decreased in BC and its activation decreases cellular proliferation, suggesting that it has a tumor-suppressive role [86]. On the other hand, overexpression of Notch2 promoted cell proliferation, EMT, invasion, and stemness maintenance, and its inhibition decreased malignant phenotypes in vitro and in vivo [87].…”

CAFs‐derived MFAP5 promotes bladder cancer malignant behavior through NOTCH2/HEY1 signaling

“…MFAP5 may activate NOTCH1 signaling by inducing NOTCH1 extracellular domain dissociation 34 . A previous study demonstrated that NOTCH2 is an oncogenic protein in bladder cancer 45 . In order to explore the role of MFAP5 in the NOCTH2 signaling pathway, we knocked down NOTCH2 in T24 and 253J cells and validated knockdown efficiency by western blot (Figure 5A).…”

Notch signaling inhibition induces G0/G1 arrest in murine Leydig cells

“…In endothelial cells, Notch signaling regulates contact inhibition and cycle arrest (Noseda et al, ). Depending on the cellular context and tissue type, the Notch pathway exerted both tumour‐suppressive and oncogenic action in cancer (Aster, ; Goriki et al, ; Nowell & Radtke, ). MK‐0752 is a potent and specific gamma‐secretase inhibitor that is widely used to prevent Notch receptor activation (Brana et al, ; Chen et al, ; Yuan et al, ).…”