Hai Fan, Dongming Yan, Xingyue Fang, Liumin Xiao, Mengjie Liang, Haolin Wu, Guohua Zhu, Dangmurenjiafu Geng, Qibing Liu
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The GEPIA database was used to select genes like GRM4. PPI network was constructed by the database of (STRING), GO and KEGG analyses were performed. TargetScan, TarBase, miRDB, and starBase were used to explore miRNAs that could regulate GRM4 expression. EWAS Data Hub, MethSurv, and MEXPRESS were used for the analysis and relationship between DNA methylation and GRM4 expression and prognosis in glioma. TIMER2.0 and CAMOIP databases were used to assess the association between immune cell infiltration and GRM4. Human GBM cell lines were used to validate the function of GRM4.</p><p><strong>Results: </strong>Our study shows that GRM4 is under expressed among gliomas and accompanied by poorer OS. Multivariate analysis showed that low mRNA expression of GRM4 was an independent factor of prognostic for shorter OS in all glioma patients. MiR-1262 affects the malignant phenotype of gliomas through GRM4. 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引用次数: 0
摘要
代谢型谷氨酸受体 4（mGlu4，GRM4）在中枢神经系统（CNS）中大量表达，并与中枢神经系统的一系列生理和病理生理过程有关。在各种癌症中，GRM4 的表达与预后不良有关。然而，有关 GRM4 在胶质瘤中作用的研究还很有限。利用癌症基因组图谱（The Cancer Genome Atlas，TCGA）、基因表达总库（Gene Expression Omnibus，GEO）和中国胶质瘤基因组图谱（China Glioma Genome Atlas，CGGA）库中的RNA测序数据集，对GRM4的表达谱与胶质瘤患者预后之间的关系进行了系统评估。利用 CGGA 和 TCGA 的临床生存数据评估了临床预后（GRM4）的价值。利用 GEPIA 数据库选择与 GRM4 相似的基因，通过 STRING 数据库构建 PPI 网络，并进行 GO 和 KEGG 分析。TargetScan、TarBase、miRDB和starBase用于探索可能调控GRM4表达的miRNA。EWAS Data Hub、MethSurv 和 MEXPRESS 用于分析胶质瘤中 DNA 甲基化与 GRM4 表达和预后之间的关系。TIMER2.0和CAMOIP数据库用于评估免疫细胞浸润与GRM4之间的关系，人类GBM细胞系用于验证GRM4的功能。我们的研究表明，GRM4在胶质瘤中表达不足，并伴随着较差的OS。多变量分析表明，在所有胶质瘤患者中，低mRNA表达（GRM4）是预示较短OS的独立因素。MiR-1262通过GRM4影响胶质瘤的恶性表型，DNA的甲基化在指导GRM4表达中起重要作用，胶质瘤组织中GRM4的甲基化水平高于正常组织，甲基化水平越高，预后越差。进一步分析表明，GRM4 mRNA在GBM中的表达与普通淋巴祖细胞、巨噬细胞M1、巨噬细胞和T细胞CD4+ Th2呈负相关，但与肿瘤纯度无关。过表达 GRM4 可阻止人类 GBM 细胞株在体外的迁移。总之，GRM4 可能对免疫细胞的浸润有重大影响，也可作为胶质瘤有价值的预后生物标志物。
Low expression of GRM4 is associated with poor prognosis and tumor immune infiltration in glioma.
Introduction: The metabotropic glutamate receptor 4 (mGlu4, GRM4) exhibits significant expression within the central nervous system (CNS) and has been implicated to be correlated with a poor prognosis.
Objective: This study was aimed to elucidate the relationship between the expression profile of GRM4 and the prognosis of glioma patients.
Methods: RNA-sequencing datasets from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and China Glioma Genome Atlas (CGGA) repositories were used to evaluate the potential relationship. The value of clinical prognostic about GRM4 was assessed using clinical survival data from CGGA and TCGA. The GEPIA database was used to select genes like GRM4. PPI network was constructed by the database of (STRING), GO and KEGG analyses were performed. TargetScan, TarBase, miRDB, and starBase were used to explore miRNAs that could regulate GRM4 expression. EWAS Data Hub, MethSurv, and MEXPRESS were used for the analysis and relationship between DNA methylation and GRM4 expression and prognosis in glioma. TIMER2.0 and CAMOIP databases were used to assess the association between immune cell infiltration and GRM4. Human GBM cell lines were used to validate the function of GRM4.
Results: Our study shows that GRM4 is under expressed among gliomas and accompanied by poorer OS. Multivariate analysis showed that low mRNA expression of GRM4 was an independent factor of prognostic for shorter OS in all glioma patients. MiR-1262 affects the malignant phenotype of gliomas through GRM4. Methylation of DNA plays an important role in the instruction of GRM4 expression, the methylation level of GRM4 in glioma tissue is higher in comparison to normal tissue, and the higher methylation level was accompanied with the worse prognosis. Further analysis showed that GRM4 mRNA expression in GBM linked negatively with common lymphoid progenitor, Macrophage M1, Macrophage, and T cell CD4+ Th2, but not with the tumor purity. Overexpression of GRM4 prevents the migration of human GBM cell lines in vitro.
Conclusion: GRM4 may have a substantial impact on the infiltration of immune cells and serve as a valuable prognostic biomarker in gliomas.
期刊介绍：
The International Journal of Neuroscience publishes original research articles, reviews, brief scientific reports, case studies, letters to the editor and book reviews concerned with problems of the nervous system and related clinical studies, epidemiology, neuropathology, medical and surgical treatment options and outcomes, neuropsychology and other topics related to the research and care of persons with neurologic disorders. The focus of the journal is clinical and transitional research. Topics covered include but are not limited to: ALS, ataxia, autism, brain tumors, child neurology, demyelinating diseases, epilepsy, genetics, headache, lysosomal storage disease, mitochondrial dysfunction, movement disorders, multiple sclerosis, myopathy, neurodegenerative diseases, neuromuscular disorders, neuropharmacology, neuropsychiatry, neuropsychology, pain, sleep disorders, stroke, and other areas related to the neurosciences.
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