Validation of the functions and prognostic values of synapse-associated proteins in lower-grade glioma

Abstract

Synapse and synapse associated proteins (SAPs) play critical roles in various neurodegeneration diseases and brain tumors. However, in lower-grade gliomas (LGG), SAPs have not been explored systematically. Herein, we are going to explore SAPs expression profile and its clinicopathological significance in LGG which can offer new insights to glioma therapy. In this study, we integrate a list of SAPs that covered 231 proteins with synaptogenesis activity and post synapse formation. The LGG RNA-seq data were downloaded from GEO, TCGA and CGGA database. The prognosis associated SAPs in key modules of PPI (protein-protein interaction networks) was regarded as hub SAPs. Western blot, quantitative reverse transcription PCR (qRT-PCR) and immunochemistry results from HPA database were used to verify the expression of hub SAPs. There were 68 upregulated SAPs and 44 downregulated SAPs in LGG tissue compared with normal brain tissue. Data from function enrichment analysis revealed functions of differentially expressed SAPs in synapse organization and glutamatergic receptor pathway in LGGs. Survival analysis revealed that four SAPs, GRIK2, GABRD, GRID2 and ARC were correlate with the prognosis of LGG patients. Interestingly, we found that GABRD were upregulated in LGG patients with seizures, indicating that SAPs may link to the pathogenesis of seizures in glioma patients. The four-SAPs signature was revealed as an independent prognostic factor in gliomas. Our study presented a novel strategy to assess the prognostic risks of LGGs, based on the expression of SAPs.

The Concept of «Peritumoral Zone» in Diffuse Low-Grade Gliomas: Oncological and Functional Implications for a Connectome-Guided Therapeutic Attitude

“…It has been suggested that the tumor cells themselves are neurotoxic (through cytokine and neurotransmitter release) and can elicit seizures by disruption of neuronal pathways or through local glutamate concentration/metabolism changes. A decrease in glutamate uptake and an increase in its release by glioma cells and by neighboring nontumoral astrocytes and activated microglia lead to an excessive glutamatergic excitatory neurotransmission and to a higher risk of seizures [28,91,96,97]. Moreover, GABAergic signaling in the PTZ, affected by the extracellular glutamate, is also involved in both glioma growth and epilepsy [25,89,91,92,[97][98][99].…”

“…Moreover, GABAergic signaling in the PTZ, affected by the extracellular glutamate, is also involved in both glioma growth and epilepsy [25,89,91,92,[97][98][99]. Additionally, alkalization of the peritumoral neocortex [87], synapse-associated proteins [28], and activation of the mammalian target of rapamycin (mTOR) pathway [25] have been implicated in epileptogenesis. Dey et al (2021) demonstrated increased spontaneous glutamatergic and GABAergic synaptic activity onto pyramidal neurons in the peritumoral samples of DLGG in patients with a history of seizures as compared with those in patients without seizures [27].…”

“…In addition, there has been increasing evidence that the associated epileptogenesis in DLGG is highly related to the increased and aberrant excitatory synapses observed in the peritumoral area [24][25][26][27][28][29], which makes it another therapeutic challenge, especially by supporting SpTR also for functional reasons since seizure control is strongly related to QoL.…”

Development and Validation of a Novel Prognostic Model for Lower-Grade Glioma Based on Enhancer RNA-Regulated Prognostic Genes

“…LGGs are some of the most common tumors in the central nervous system. However, the heterogeneity and complexity of these tumors have delayed the development of specific and effective predictive biomarkers for LGGs ( 21 , 22 ). An effective prognostic model based on specific biomarkers could accurately forecast survival outcomes, allowing efficient management of patients with LGGs.…”

Prognostic value of γ‐aminobutyric acidergic synapse-associated signature for lower-grade gliomas

“…The CNS is also rich in neurotransmitters, which create a unique microenvironment for brain tumors, where neurotransmitter-mediated intracellular signaling pathways can be transduced by cancer cells and induce cancer cell growth, activation, and metastasis ( 7 ). With the progressive discovery of glioma synapses and metastatic neuronal synapses, it is believed that neurotransmitters may play crucial roles in tumor growth, and the speculation that tumor cells may stimulate their innervation has been confirmed ( 8 , 9 ). It has been suggested that microenvironment interaction, especially the abnormal interaction between glial cells and synapses, is one of the neuropathological mechanisms underlying Rett syndrome, Down syndrome, spinal muscular atrophy, and other diseases ( 10 ).…”