Abstract
Notch signaling, an evolutionarily conserved signaling cascade system, is involved in promoting the progression of different types of cancers. Within the past decades, the Notch signaling pathway has increasingly been shown to have a primary role in deciding the fate of cancer cells and cancer stem cells in the stomach. Most components of Notch signaling are strongly expressed at different levels in gastric carcinoma tissue samples and are associated with a considerable number of clinical parameters. Moreover, crosstalk signaling between the Notch pathway and the Wnt, Ras, and NF-κB pathways promotes the process of gastric carcinogenesis. Consequently, this increases proliferation and prevents apoptosis in gastric cancer cells, and it contributes to the induction of angiogenesis and accelerates the progression of the epithelial-to-mesenchymal transition. Although the Notch signaling pathway presents novel therapeutic targets for cancer therapeutic intervention, there is still a dearth of in-depth understanding of the molecular mechanisms of Notch signaling in gastric carcinoma. In this review, we summarize the landscape of the Notch signaling pathway and recent findings on Notch signaling in gastric cancer. Furthermore, advanced studies and clinical treatments targeting the Notch signaling pathway arediscussed.
Highlights
Despite the declining incidence of gastric carcinoma, it remains one of the most common malignancies and the second largest cause of cancer-related deaths in the world [1, 2]
Crosstalk signaling between the Notch pathway and the Wnt, Ras, and NF-κB pathways promotes the process of gastric carcinogenesis
We summarize the landscape of the Notch signaling pathway and recent findings on Notch signaling in gastric cancer
Summary
Despite the declining incidence of gastric carcinoma, it remains one of the most common malignancies and the second largest cause of cancer-related deaths in the world [1, 2]. After two successive proteolytic cleavages, mediated by ADAM/TACE at the extracellular domain and the γ-secretase complex at the transmembrane region, the Notch intracellular domain (NICD) is released into the cytoplasm. It translocates into the cytoblast and combines with the transcriptional repressor C-promoter binding factor-1(CBF1 in human know as CSL) to replace a co-repressor complex. The 300 kDa precursor of the Notch receptor is cleaved at site 1 (S1) by furin-like convertases within the trans-Golgi network [23] This produces a heterodimeric receptor consisting of a C-terminal fragment membranetethered intracellular domain (NTM) and an N-terminus N(EC) that contains most of the extracellular region, which is transported to the cytomembrane, followed by ligand-receptor binding and endocytosis [24]. GSIs are a sort of exogenous chemosynthetic inhibitors (such as DAPT, MRK003, RO4929097, LY411575, MK0752, etc.) that block proteolytic cleavage of Notch by targeting γ-secretase and subsequently reduce activation of NICD and downstream effectors
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