Notch and its oncogenic activity in human malignancies

Abstract

SummaryBackgroundIncreasing evidence has demonstrated that Notch signaling is deregulated in human hematological malignancies and solid tumors. This signaling has a protumorigenic effect but may also act as a tumor suppressor. How induction of a single pathway gives rise to the opposite effects in different cell types is still unknown.MethodsThis review article includes available data from peer-reviewed publications associated with the role of Notch signaling during cancer pathogenesis.ResultsNumerous reports have indicated that alterations in Notch signaling and its oncogenic activity were originally associated with the pathogenesis of T‑cell acute lymphoblastic leukemia/lymphoma (T-ALL), an aggressive hematologic tumor affecting children and adolescents. The possibility that Notch could play a significant role in human breast cancer development comes from studies on mouse mammary tumor virus-induced cancer. Numerous findings over the past several years have indicated that alterations in Notch signaling are also responsible for ovarian cancer development. Mention should also be made of the connection between expression of Notch 3 and increased resistance to chemotherapy, which remains a major obstacle to successful treatment. Notch as an oncogenic factor is also involved in the development of colon cancer, lung carcinoma and Kaposi’s sarcoma.ConclusionNotch is a binary cell fate determinant and its overexpression has been described as oncogenic in a wide array of human malignancies. This finding led to interest in therapeutically targeting this pathway, especially by the use of gamma-secretase inhibitors (GSIs) blocking the cleavage of Notch receptors at the cell membrane by the inhibition of Notch intracellular domain (NICD) releasing. Preclinical cancer models have revealed that GSIs suppress the growth of cancers such as pancreatic, breast and lung cancer.

Merkel Cell Polyomavirus Small Tumor Antigen Activates Matrix Metallopeptidase-9 Gene Expression for Cell Migration and Invasion

“…It has been demonstrated that loss of FBW7 induces Notch1 and Notch1 downstream molecules (MMP-2 and MMP-9) activation, resulting in induced-cell migration and invasion in hepatocellular carcinoma (HCC) (22). Similar trends have been observed in breast cancer where Notch1 signaling promotes an invasive phenotype as a result of activation of NF-κB and its downstream target genes including MMP-2, MMP-9 (59), while downregulation of Notch-1 decreases MMP-9 transcription and function (60). Nonetheless, it is clear that MCV sT LSD plays a critical role in regulating transcriptional and post-translational MMP-9 expression and activity.…”

Gliquidone Alleviates Diabetic Nephropathy by Inhibiting Notch/Snail Signaling Pathway

“…Mammals have 4 Notch receptors and 5 Notch ligands. Notch ligands from adjacent cells bind to their counterparts, and after three enzymatic cleavages, they are released into the cytoplasm and nucleus, and bind to the gene of interest to form a transcriptional activation complex that activates the target gene of the transcriptional repressor family (HES , HEY, HERP and other basic-helix-loop-helix (bHLH)) [24]. Notch signaling pathway is involved in regulation of various diseases, including the majority of kidney diseases and glomerular diseases.…”

Predictive Value of Pin1 in Cervical Low-Grade Squamous Intraepithelial Lesions and Inhibition of Pin1 Exerts Potent Anticancer Activity against Human Cervical Cancer

“…Current research has indicated that blocking a single pathway is often ineffective for the treatment of solid tumors [42]. As a regulator of phosphor-proteins with the Ser/Thr-Pro motif, Pin1 regulates multiple cancer-driving pathways in CCCs [9].…”