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术中瘤周组织 RNA 测序揭示胶质细胞瘤相关癫痫相关的潜在途径。

RNA Sequencing of Intraoperative Peritumoral Tissues Reveals Potential Pathways Involved in Glioma-Related Seizures.

机构信息

Department of Neurology, AIIMS, New Delhi, India.

Department of Biophysics, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029, India.

出版信息

J Mol Neurosci. 2023 Jun;73(6):437-447. doi: 10.1007/s12031-023-02125-y. Epub 2023 Jun 2.

Abstract

Tumor-induced changes in the peritumoral neocortex play a crucial role in generation of seizures. This study aimed to investigate the molecular mechanisms potentially involved in peritumoral epilepsy in low-grade gliomas (LGGs). Intraoperative peritumoral brain tissues resected from LGG patients with seizures (pGRS) or without seizures (pGNS) were used for RNA sequencing (RNA-seq). Comparative transcriptomics was performed to identify differentially expressed genes (DEGs) in pGRS compared to pGNS using deseq2 and edgeR packages (R). Gene set enrichment analysis (GSEA) using Gene Ontology terms and Kyoto Encyclopedia of Genes & Genomes (KEGG) pathways was performed using the clusterProfiler package (R). The expression of key genes was validated at the transcript and protein levels in the peritumoral region using real-time PCR and immunohistochemistry, respectively. A total of 1073 DEGs were identified in pGRS compared to pGNS, of which 559 genes were upregulated and 514 genes were downregulated (log2 fold-change ≥ 2, padj < 0.001). The DEGs in pGRS were highly enriched in the "Glutamatergic Synapse" and "Spliceosome" pathways, with increased expression of GRIN2A (NR2A), GRIN2B (NR2B), GRIA1 (GLUR1), GRIA3 (GLUR3), GRM5, CACNA1C, CACNA1A, and ITPR2. Moreover, increased immunoreactivity was observed for NR2A, NR2B, and GLUR1 proteins in the peritumoral tissues of GRS. These findings suggest that altered glutamatergic signaling and perturbed Ca homeostasis may be potential causes of peritumoral epilepsy in gliomas. This explorative study identifies important genes/pathways that merit further characterization for their potential involvement in glioma-related seizures.

摘要

肿瘤诱导的瘤周新皮层改变在致痫发作中起关键作用。本研究旨在探讨低级别胶质瘤(LGG)瘤周癫痫发生中潜在的分子机制。对有癫痫发作(pGRS)或无癫痫发作(pGNS)的 LGG 患者手术切除的瘤周脑组织进行 RNA 测序(RNA-seq)。使用 deseq2 和 edgeR 包(R)比较 pGRS 与 pGNS 之间的差异表达基因(DEGs)。使用 clusterProfiler 包(R)对基因集富集分析(GSEA)进行基因本体论(GO)术语和京都基因与基因组百科全书(KEGG)途径分析。使用实时 PCR 和免疫组织化学分别在瘤周区域验证关键基因的转录和蛋白水平的表达。与 pGNS 相比,pGRS 中鉴定出 1073 个 DEGs,其中 559 个基因上调,514 个基因下调(log2 倍数变化≥2,padj<0.001)。pGRS 中的 DEGs 高度富集于“谷氨酸能突触”和“剪接体”途径,GRIN2A(NR2A)、GRIN2B(NR2B)、GRIA1(GLUR1)、GRIA3(GLUR3)、GRM5、CACNA1C、CACNA1A 和 ITPR2 的表达增加。此外,在 GRS 的瘤周组织中观察到 NR2A、NR2B 和 GLUR1 蛋白的免疫反应性增加。这些发现表明,谷氨酸能信号转导改变和钙稳态失调可能是胶质瘤瘤周癫痫发生的潜在原因。这项探索性研究确定了重要的基因/途径,值得进一步表征其在胶质瘤相关癫痫中的潜在作用。

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