Significance of NotchScore and JAG1 in predicting prognosis and immune response of low-grade glioma

Abstract

IntroductionLow-grade glioma (LGG) is a prevalent malignant tumor in the intracranial region. Despite the advancements in treatment methods for this malignancy over the past decade, significant challenges still persist in the form of drug resistance and tumor recurrence. The Notch signaling pathway plays essential roles in many physiological processes as well as in cancer development. However, the significance of the pathway and family genes in LGG are poorly understood. MethodsWe conducted gene expression profiling analysis using the TCGA dataset to investigate the gene set associated with the Notch signaling pathway. we have proposed a metric called "NotchScore" that quantifies the strength of the Notch signaling pathway and enables us to assess its significance in predicting prognosis and immune response in LGG. We downregulated JAG1 in low-grade gliomas to assess its influence on the proliferation and migration of these tumors. Ultimately, we determined the impact of the transcription factor VDR on the transcription of PDL1 through chip-seq data analysis.ResultsOur findings indicate that tumors with a higher NotchScore, exhibit poorer prognosis, potentially due to their ability to evade the anti-tumor effects of immune cells by expressing immune checkpoints. Among the genes involved in the Notch signaling pathway, JAG1 has emerged as the most representative in terms of capturing the characteristics of both NotchScore and Notch pathways. The experimental results demonstrate that silencing JAG1 yielded a significant decrease in tumor cell proliferation in LGG cell lines. Our study revealed mechanisms by which tumors evade the immune system through the modulation of PDL1 transcription levels via the PI3K-Akt signaling pathway. Additionally, JAG1 potentially influences PDL1 in LGG by regulating the PI3K-Akt signaling pathway and the expression of the transcription factor VDR.DiscussionThese findings contribute to our understanding of immune evasion by tumors in LGG. The insights gained from this research may have implications for the development of therapeutic interventions for LGG.

Identification of Key Molecular Pathways and Associated Genes as Targets to Overcome Radiotherapy Resistance Using a Combination of Radiotherapy and Immunotherapy in Glioma Patients

“…JAG1 was significantly downregulated in the RT plus CSF-1R inhibition group compared with the recurrent RT-treated mice. High levels of JAG1 and NOTCH1/DLL1 were significantly positively associated with short survival in the TCGA cohort, which was consistent with findings in literature [ 18 , 19 ]. Importantly, it has been shown that [ 18 ], Notch1 signaling activity was elevated in GBM tissues, and downregulation of the Notch1 pathway by shRNA and MK0752 significantly inhibited the PI3K/AKT/mTOR signaling pathway and weakened the self-renewal, invasion, and tumor growth ability of glioma initiating cells.…”

“…This is one of the potential mechanisms underlying the combination therapy (RT plus CSF-1R inhibition) that seemingly mitigated resistance to RT-only [ 12 ] and CSF-1R inhibition-only therapy [ 3 ]. Additionally, experimental results demonstrate that silencing JAG1 yielded a significant decrease in tumor cell proliferation in LGG cell lines, and JAG1 potentially influences PD-L1 in LGG by regulating the PI3K/AKT signaling pathway [ 19 ]. The critical role of the Hippo pathway has been investigated in GBM, and the results suggested that the activation of YAP1/WWTR1 was associated with poor prognosis in GBM [ 20 ].…”