| Background and aimDiffuse glioma is the most common malignant neuroepithelial tumor with high disability,high recurrence,and poor survival prognosis.Patients have limited benefit from traditional treatment but there is still no effective targeted therapy.Therefore,exploring new biomarkers can help to understand glioma pathogenesis and design new drugs.Synapse and Synapse associated proteins(SAPs)have been found to play significant roles in various neurodegenerative diseases(Alzheimer’s disease and Parkinson’s disease)and intracranial tumors such as glioblastoma(GBM)and brain metastases.However,the expression and function of SAPs in grade Ⅱ/Ⅲ gliomas have not been studied before.This article aims to explore the expression of SAPs in grade Ⅱ/Ⅲ gliomas and their prognostic value,providing novel strategy for the treatment of gliomas.MethodThis study integrated a list of 231 proteins about synaptogenesis activity or postsynaptic composition.Using the Rembrandt and Henry Ford Hospital cohort,this study screened out differentially expressed SAPs.After analyzing the functions of the differentially expressed SAPs,these SAPs were further analyzed in the protein interaction network(PPI).Survival analysis were used to searching for hub SAPs from the SAPs in key modules of PPI.Mutation and copy-number alteration data for all hub SAPs were identified in the GISTIC database.Western blot,quantitative reverse transcription PCR(q RT-PCR)and immunochemistry results from HPA database were used to verify the expression of hub SAPs.ResultCompared with normal brain tissue,there were 68 upregulated SAPs and 44 downregulated SAPs in grade Ⅱ/Ⅲ gliomas.Functional enrichment analysis(GO and KEGG analysis)revealed that differentially expressed SAPs are enrich in synapses and glutamatergic receptor pathway in grade Ⅱ/Ⅲ glioma.Through multivariate logistic regression analysis,four hub SAPs with prognostic significance were found out:GRIK2(OR=0.80,P=0.014),GABRD(OR=0.79,P<0.001),GRID2(OR=0.73,P<0.001)and ARC(OR =1.32,P<0.001).Among them,GRID2,GRIK2,and ARC were upregulated in grade Ⅱ/Ⅲ gliomas,while GABRD was downregulated in grade Ⅱ/Ⅲ gliomas.Interestingly,this study showed that the expression of GABRD was upregulated in grade Ⅱ/Ⅲ glioma patients with seizures.Furthermore,this study constructed a prognostic model based on the expression of four SAPs.This four-SAPs signature was proved to has a good ability to predict the prognosis of grade Ⅱ/Ⅲ glioma.ConclusionThe discovery of glioma-to-neurons synapses provides people a novel prospective on the mechanism of glioma progression.Four synapse-related proteins(GRID2,GRIK2,GABRC and ARC)were found to be important biomarkers of grade Ⅱ/Ⅲ gliomas.Furthermore,this study suggested that SAPs may be related to the pathogenesis of seizures in glioma patients.Last but not less,this study proposes a prognostic model based on the expression of SAPs,which will be useful to clinician. |
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