Notch signalling pathway as an oncogenic factor involved in cancer development

Abstract

Notch signalling is an evolutionarily conserved signalling pathway, which plays a significant role in a wide array of cellular processes including proliferation, differentiation, and apoptosis. Nevertheless, it must be noted that Notch is a binary cell fate determinant, and its overexpression has been described as oncogenic in a broad range of human malignancies. This finding led to interest in therapeutically targeting this pathway especially by the use of GSIs, which block the cleavage of Notch at the cell membrane and inhibit release of the transcriptionally active NotchIC subunit. Preclinical cancer models have clearly demonstrated that GSIs suppress the growth of such malignancies as pancreatic, breast, and lung cancer; however, GSI treatment in vivo is associated with side effects, especially those within the gastrointestinal tract. Although intensive studies are associated with the role of γ-secretase in pathological states, it should be pointed out that this complex impacts on proteolytic cleavages of around 55 membrane proteins. Therefore, it is clear that GSIs are highly non-specific and additional drugs must be designed, which will more specifically target components of the Notch signalling.

STAT3-induced upregulation of long noncoding RNA HNF1A-AS1 promotes the progression of oral squamous cell carcinoma via activating Notch signaling pathway

“…37 The regulatory function of Notch signaling in genes' expression often promote tumor formation. 40 Therefore, in this study, we explored the regulatory relationship between HNF1A-AS1 and Notch signaling in OSCC. We found that both HNF1A-AS1 and Notch signaling were upregulated in OSCC cells.…”

Spica Prunellae extract suppresses the growth of human colon carcinoma cells by targeting multiple oncogenes via activating miR-34a

“…With miR-34a upregulation, its target genes Notch1, Notch2 and Bcl-2 were repressed following EESP treatment. Since these target genes were oncogenes and had apoptosis-targeting therapeutic potential in cancers (45)(46)(47), the results suggested that EESP might suppress growth of human colon carcinoma cells through promoting cell apoptosis by targeting Notch1, Notch2 and Bcl-2 via activating miR-34a ( Fig. 5).…”

Crosstalk between the Notch signaling pathway and non‑coding RNAs in gastrointestinal cancers (Review)

“…Further studies are required to explore the structure and functional features of these ncRNAs, as well as their effects on malignancies. In therapy, contraposing the oncogenic potential of Notch signaling, Notch inhibitors including γ-secretase inhibitors (GSIs), are effective in inhibiting Notch signaling (4). GSIs have been demonstrated to prevent cell proliferation, migration and invasion in pancreatic cancer (100).…”

“…Based on its influence on various downstream functions, Notch signaling may serve oncogenic and anti-tumor functions in different types of human cancer, depending on the cellular context (22)(23)(24). In specific types of tumor or tumor stages, aberrant Notch signaling is involved in cancer recurrence, metastasis, epithelial to mesenchymal transition (EMT) and resistance to treatment (4,(25)(26)(27)(28).…”

“…Furthermore, the abnormal activation of Notch signaling may result from the mutation or amplification of Notch signaling components (1). As Notch signaling may regulate a plethora of genes, the dysregulation of Notch signaling often promotes tumor formation (4).…”