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Detection of lower levels of SNAP25 using multiple microarray systems and its functional significance in medulloblastoma

ABSTRACT: Medulloblastoma (MB) is the most common pediatric malignant brain tumor and patients with a high-risk or recurrent MB respond poorly to current therapies, with higher related mortality. Potential molecules related to MB must be identified to develop targets for therapeutic development. In the present study, we compared MB microarray data obtained using different microarray systems and significant targets were selected by gene annotation and enrichment analysis. Genes for soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) annotated with the function “vesicle” were identified and one of these proteins, synaptosomal-associated protein 25 (SNAP25), had significantly lower expression levels in MB. In addition, SNAP25 was detected in a very low number of MB cells according to western blot analysis and immunohistochemical analyses of archived and formalin-fixed/paraffin-embedded human MB specimens. We found that SNAP25 could change the morphology and the chemotherapeutic effect of arabinofuranosyl cytidine (Ara-C) on SNAP25-expressing MB cells. In conclusion, the expression of SNAP25 is crucial for the dendrite formation and correlate to the targeted chemotherapy. The detection of SNAP25 expression in MB cells may be essential for the chemotherapeutic application of Ara-C.

ORGANISM(S): Homo sapiens

PROVIDER: GSE74947 | GEO | 2015/11/13

SECONDARY ACCESSION(S): PRJNA301990

REPOSITORIES: GEO

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Project description:INTRODUCTION: Neuronal 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 one of these proteins, synaptosomal-associated protein 25 (SNAP25), was found to have discrepant expression levels in neuropathies. However, the specific mechanism and prognostic value of SNAP25 during glioma progression remain unclear. METHODS: Using RNA sequencing data from The Cancer Genome Atlas (TCGA) database, the differential synaptosis-related genes between LGG and GBM were identified as highly correlated. Cox proportional hazards regression analysis and survival analysis indicated that the candidate gene SNAP25 could 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. Then, an immunofluorescence assay of the xenograft tissue was applied to evaluate the expression of the neuronal dendron formation marker-MAP2. Liquid chromatography-high re solution 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.RESULTS: SNAP25 was down expressed 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 glutamate metabolism of glioma cells, exerting a tumor suppressor role. SNAP25 overexpression expressed lower expression of MAP2, indicating poor neuronal plasticity and connectivity. SNAP25 could interact with glutaminase（GLS）and GLS knockdown could rescue the anti-tumor effect of SNAP25 in glioma cells. Moreover, upregulation of SNAP25 also decreased tumor volume and prolonged the overall survival (OS) of the xenograft mouse.CONCLUSION: SNAP25 inhibited carcinogenesis of glioma via sponging glutamate metabolism by regulating GLS expression, as well as inhibiting dendritic formation, which could be considered as a molecular target for glioma diagnosis and therapy.

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Detection of lower levels of SNAP25 using multiple microarray systems and its functional significance in medulloblastoma

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