Section 3.2.2: Notch signaling pathway in CSCs (from DOI: 10.1038/s41392-020-0110-5)
From publication: "Targeting cancer stem cell pathways for cancer therapy" published as Signal Transduct Target Ther; 2020 ; 5 8; DOI: https://doi.org/10.1038/s41392-020-0110-5
Section 3.2.2: Notch signaling pathway in CSCs
The Notch signaling pathway consists of the Notch receptor, Notch ligand (DSL protein), CSL (CBF-1, suppressor of hairless, Lag), DNA-binding protein, other effectors, and Notch regulatory molecules. In 1917, studies discovered the Notch gene in a mutant Drosophila. Mammals have four Notch receptors (Notch1-4) and five Notch ligands (Delta-like 1, 3, and 4, Jagged 1, and Jagged 2). Notch and DSL ligands are transmembrane proteins that mediate communication between neighboring cells. Under physiological conditions, the ligand binds to a Notch receptor that is expressed on neighboring cells in a juxtacrine manner, thereby triggering proteolytic cleavage of the intracellular domain (ICD) of Notch and its translocation into the nucleus to bind to the transcription factor CSL, forming the NICD/CSL transcriptional activation complex, which activates target genes of the bHLH transcription inhibitor family, such as HES, HEY, and HERP.
The Notch pathway regulates cancer cells in many tumors, such as glioblastoma, leukemia, and those of the breast, pancreas, colon, and lung, among others. Different tumors and tumor subtypes express different Notch ligands and receptors. Therefore, Notch is known to function as both an oncogene and a suppressive gene. As an oncogene, Notch is overexpressed in gastric cancer, breast cancer, colon cancer, and pancreatic cancer. In contrast, Notch expression is downregulated in prostate cancer, skin cancer, non-small-cell lung cancer, liver cancer, and some breast cancers. Whether Notch acts as an oncogene or a tumor suppressor gene is determined by the microenvironment. Moreover, post-translational modifications of Notch receptors change their affinity for ligands and their intracellular half-lives.
Many studies on the Notch pathway in CSCs have shown that activation of Notch promotes cell survival, self-renewal, and metastasis and inhibits apoptosis. Aberrant Notch signaling (Notch1 and Notch4) promotes self-renewal and metastasis of breast and HCC stem cells. However, microRNA-34a downregulates Notch1. Similarly, abundant Delta-like ligand 4 (DLL4) also promotes tumor angiogenesis and metastasis in gastric CSCs. Delta-like 1 activation of Notch1 signaling requires the assistance of the actin-related protein 2/3 complex to maintain the stem cell phenotype of glioma-initiating cells. Additionally, some intracellular genes also regulate the Notch signaling pathway. For example, MAP17 (DD96, PDZKIP1), a nonglycosylated membrane-associated protein, is located on the plasma membrane and the Golgi apparatus. MAP17 interacts with NUMB through the PDZ-binding domain to activate the Notch pathway in cervical CSCs. Inducible nitric oxide synthase promotes the self-renewal capacity of CD24+CD133+ liver CSCs through TACE/ADAM17 activation to regulate Notch1 signaling. Moreover, tumor necrosis factor-alpha (TNFalpha) enhances the CSC-like phenotype by activating Notch1 signaling in oral SCC cells. Overexpression of PER3 decreases the expression of Notch1 and Jagged 1 in colorectal CSCs. In addition, KLF4 and BMP4 also increase Notch1 and Jagged 1 in breast CSCs to regulate cell migration and invasion. BRCA1 is a key regulator of breast cancer cell differentiation; however, it is localized to a conserved intronic enhancer region within the Notch ligand Jagged 1 gene to maintain the stemness of breast CSCs. Similarly, increased Gli3 also promotes cell proliferation and invasion in oral SCC by increasing Notch2. Hypoxia/hypoxia-inducible factor (HIF)-induced migration and invasion is a well-known phenomenon that has been reported in numerous CSCs. Notch1 can induce the migration and invasion of ovarian CSCs in the absence of hypoxia. Hypoxia-induced Jagged 2 activation enhances cell invasion of breast CSCs and lung CSCs. Moreover, HIF-1alpha/2alpha regulates self-renewal and maintenance of glioblastoma stem cells. In addition, increased miR-200b-3p decreases Notch signaling to promote pancreatic CSCs to become asymmetric. MiR-26a directly targets Jagged 1 to inhibit osteosarcoma CSC proliferation. These studies indicate that Notch plays an important role in regulating the self-renewal, growth, and metastasis of CSCs.
