Abstract
BackgroundNeuronal activity regulated by synaptic communication exerts an important role in tumorigenesis and progression in brain tumors. Genes for soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) annotated with the function ‘vesicle’ about synaptic connectivity were identified, and synaptosomal-associated protein 25 (SNAP25), one of those proteins, was found to have discrepant expression levels in neuropathies. However, the specific mechanism and prognostic value of SNAP25 during glioma progression remain unclear.MethodsUsing RNA sequencing data from The Cancer Genome Atlas (TCGA) database, the differential synaptosis-related genes between low grade glioma (LGG) and glioblastoma (GBM) were identified as highly correlated. Cox proportional hazards regression analysis and survival analysis were used to differentiate the outcome of low- and high-risk patients, and the Chinese Glioma Genome Atlas (CGGA) cohort was used for validation of the data set. RT-qPCR, western blot, and immunohistochemistry assays were performed to examine the expression level of SNAP25 in glioma cells and samples. Functional assays were performed to identify the effects of SNAP25 knockdown and overexpression on cell viability, migration, and invasion. Liquid chromatography-high resolution mass spectrometry (LC-MS)-based metabolomics approach was presented for identifying crucial metabolic disturbances in glioma cells. In situ mouse xenograft model was used to investigate the role of SNAP25 in vivo. Then, an immunofluorescence assay of the xenograft tissue was applied to evaluate the expression of the neuronal dendron formation marker-Microtubule Associated Protein 2 (MAP2).ResultsSNAP25 was decreased in level of expression in glioma tissues and cell lines, and low-level SNAP25 indicated an unfavorable prognosis of glioma patients. SNAP25 inhibited cell proliferation, migration, invasion and fostered glutamine metabolism of glioma cells, exerting a tumor suppressor role. Overexpressed SNAP25 exerted a lower expression level of MAP2, indicating poor neuronal plasticity and connectivity. SNAP25 could regulate glutaminase (GLS)-mediated glutaminolysis, and GLS knockdown could rescue the anti-tumor effect of SNAP25 in glioma cells. Moreover, upregulated SNAP25 also decreased tumor volume and prolonged the overall survival (OS) of the xenograft mouse.ConclusionSNAP25, a tumor suppressor inhibited carcinogenesis of glioma via limiting glutamate metabolism by regulating GLS expression, as well as inhibiting dendritic formation, which could be considered as a novel molecular therapeutic target for glioma.
Highlights
Gliomas are among the most common primary brain tumors in adults and account for over 70% of malignant brain tumors, of which glioblastoma (GBM) is the most aggressive and deadly type with a median survival of 15 months and 5-year overall survival of 5.5% [1]
Recent progress in molecular profiling has improved the diagnostics and classification system in which the most significant knowledge is that somatic mutations affecting the R132 residue of the isocitrate dehydrogenase 1 (IDH1) or R172 residue of the isocitrate dehydrogenase 2 (IDH2) are often detected in WHO II or III gliomas and oligodendrogliomas [26]
synaptosomalassociated protein 25 (SNAP25), a member of the sensitive factor attachment protein receptors (SNAREs) family, is a membrane-binding protein in neurons that plays an indispensable role in the occurrence and development of various synaptopathies [18, 27]
Summary
Gliomas are among the most common primary brain tumors in adults and account for over 70% of malignant brain tumors, of which glioblastoma (GBM) is the most aggressive and deadly type with a median survival of 15 months and 5-year overall survival of 5.5% [1]. Cancer cells typically rewire their metabolism to meet the bioenergetic and biosynthetic demands of uncontrolled cell growth, for example, many oncogenic mutations result in enhanced glutamate metabolism, reflecting its importance on tumor progression by generating tricarboxylic acid (TCA) cycle intermediates and amino acids, and maintaining redox homeostasis [15, 16]. In this context, the rate-limiting enzyme converting glutamine to glutamate, GLS, primarily enhances glutaminolysis and may provide a typical target in glutamate metabolism pathways [17]. The specific mechanism and prognostic value of SNAP25 during glioma progression remain unclear
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