Role of Notch Signaling Pathway in Glioblastoma Pathogenesis
Role of Notch Signaling Pathway in Glioblastoma Pathogenesis
Ghazal Azizi,1,*
1. Msc of Molecular Genetic Department of Genetics, Zanjan Branch, Islamic Azad University, Zanjan, Iran.
Introduction: The most prevalent and lethal primary brain tumor is glioblastoma. It is categorized as a Grade IV astrocytoma by the World Health Organization and accounts for 70% of all gliomas. Cell proliferation, apoptosis, stem cell maintenance, cell fate determination, and tissue homeostasis are just a few of the physiological and developmental activities that Notch signaling is essential. This system has been retained throughout evolution. Mammals have four homologous proteins called Notch1, Notch2, Notch3, and Notch4 that operate as cytoplasmic receptors and can bind the ligand families Jagged (Jagged1 and -2) and Delta-like (Dll1-3 and -4). They are single-pass transmembrane proteins, as are the receptors and ligands. The interaction between Notch and its ligands can occur in two ways: In trans, when they are present on neighbouring cells, or in cis when the receptor and ligand are present on the same cell. In the first case, binding leads to pathway activation, while in cis form interaction inhibits the signaling cascade. The aim of this study was to investigate the Role of the Notch Signaling Pathway in Glioblastoma Pathogenesis.
Methods: Scientific databases like Science Direct, Springer, Google Scholar, and PubMed were used for this review study.
Results: mRNA and protein levels of Notch1, Notch4, Dll1, Dll4, Jagged1, CBF1, Hey1, Hey2, and Hes1 are higher in brain tumor cells than normal brain cells, correlating with an elevated expression of VEGF and pAKT, and reduced levels of PTEN. In particular, Notch1 expression is higher in the survival of > 1-year patients than <1 year, whereas Notch1 overexpression is associated with low overall survival (OS), suggesting a controversial role of Notch1 in glioma genesis. Moreover, Notch1 is more expressed in peritumor-tissue GSCs compared to tumor-core GSCs. Notch1 and Notch4 levels correlate with those of GFAP and vimentin, respectively. Notch4 expression increases with higher-grade and primary tumors. Notch2 expression levels in Glioblastoma tissue correlate with stemness genes (nestin, SOX2), astrocyte fate genes (vimentin and GFAP), and anti-apoptotic proteins (BCL6 and BCL-W), but are inversely correlated with Olig2, CNP, and PLP1 (oligodendrocyte fate) and pro-apoptotic proteins (BAX and BCLAF1). The overexpression of Hey1, which is associated with survival and tumor grade, might be due to the impairment of Notch and E2F signaling; it was demonstrated that its overexpression in NSCs triggers neurosphere formation and contributes to Glioblastoma proliferation [95]. On the contrary, several groups reported a weak expression of Notch1, Notch2, MAML1, and p300 in Glioblastoma. Intriguingly, the impairment of Notch signaling in secondary Glioblastoma, in which Hes1 expression is almost absent, is associated with the overexpression of ASCL1. On the other hand, the activation of Notch signaling in primary Glioblastoma is associated with low levels of ASCL1, suggesting that Notch inhibition via ASCL1 upregulation might be responsible for a potential progression into secondary Glioblastomas. Correlation between Glioblastoma molecular subtypes and Notch expression was also demonstrated. Concerning the mesenchymal subtype (the most aggressive one), Notch-related genes are the most highly enriched in high p-STAT3 patients, suggesting a synergy between Notch and STAT3 signaling. Verhaak et al. reported that Notch signaling is highly expressed in the classic subtype. The expression levels of Dll3 and Hey2 are low in proneural Glioblastomas, while the expression level of Notch1 is high.
Conclusion: Finally, even the non-canonical Notch pathway contributes to the development of gliomas. The findings demonstrated that Deltex1 (DTX1) levels were higher in glioblastoma than in healthy brain tissue, causing many pathways involved in glioma aggression, including RTK/PI3K/PKB and MAPK/ERK signaling, as well as the anti-apoptotic protein Mcl-1.