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长链非编码 RNA 相关 ceRNA 网络的综合分析揭示胶质母细胞瘤中新型潜在预后调控轴。

Comprehensive analysis of lncRNA-associated ceRNA network reveals novel potential prognostic regulatory axes in glioblastoma multiforme.

机构信息

Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Student Research Committee, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

出版信息

J Cell Mol Med. 2024 Jun;28(11):e18392. doi: 10.1111/jcmm.18392.

DOI:10.1111/jcmm.18392
PMID:38864705
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11167707/
Abstract

Deciphering the lncRNA-associated competitive endogenous RNA (ceRNA) network is essential in decoding glioblastoma multiforme (GBM) pathogenesis by regulating miRNA availability and controlling mRNA stability. This study aimed to explore novel biomarkers for GBM by constructing a lncRNA-miRNA-mRNA network. A ceRNA network in GBM was constructed using lncRNA, mRNA and miRNA expression profiles from the TCGA and GEO datasets. Seed nodes were identified by protein-protein interaction (PPI) network analysis of deregulated-mRNAs (DEmRNAs) in the ceRNA network. A lncRNA-miRNA-seed network was constructed by mapping the seed nodes into the preliminary ceRNA network. The impact of the seed nodes on the overall survival (OS) of patients was assessed by the GSCA database. Functional enrichment analysis of the deregulated-lncRNAs (DElncRNA) in the ceRNA network and genes interacting with OS-related genes in the PPI network were performed. Finally, the positive correlation between seed nodes and their associated lncRNAs and the expression level of these molecules in GBM tissue compared with normal samples was validated using the GEPIA database. Our analyzes revealed that three novel regulatory axes AL161785.1/miR-139-5p/MS4A6A, LINC02611/miR-139-5p/MS4A6A and PCED1B-AS1/miR-433-3p/MS4A6A may play essential roles in GBM pathogenesis. MS4A6A is upregulated in GBM and closely associated with shorter survival time of patients. We also identified that MS4A6A expression positively correlates with genes related to tumour-associated macrophages, which induce macrophage infiltration and immune suppression. The functional enrichment analysis demonstrated that DElncRNAs are mainly involved in neuroactive ligand-receptor interaction, calcium/MAPK signalling pathway, ribosome, GABAergic/Serotonergic/Glutamatergic synapse and immune system process. In addition, genes related to MS4A6A contribute to immune and inflammatory-related biological processes. Our findings provide novel insights to understand the ceRNA regulation in GBM and identify novel prognostic biomarkers or therapeutic targets.

摘要

解析长链非编码 RNA（lncRNA）相关竞争性内源性 RNA（ceRNA）网络对于通过调节 miRNA 的可用性和控制 mRNA 的稳定性来解码胶质母细胞瘤（GBM）的发病机制至关重要。本研究旨在通过构建 lncRNA-miRNA-mRNA 网络来探索 GBM 的新型生物标志物。使用 TCGA 和 GEO 数据集的 lncRNA、mRNA 和 miRNA 表达谱构建 GBM 的 ceRNA 网络。通过 ceRNA 网络中失调的信使 RNA（DEmRNAs）的蛋白质-蛋白质相互作用（PPI）网络分析鉴定种子节点。通过将种子节点映射到初步的 ceRNA 网络中构建 lncRNA-miRNA-种子网络。GSCA 数据库评估种子节点对患者总生存期（OS）的影响。对 ceRNA 网络中失调的长链非编码 RNA（DElncRNA）和 PPI 网络中与 OS 相关基因相互作用的基因进行功能富集分析。最后，使用 GEPIA 数据库验证种子节点与其相关 lncRNA 之间的正相关性以及这些分子在 GBM 组织与正常样本中的表达水平。我们的分析表明，三个新的调控轴 AL161785.1/miR-139-5p/MS4A6A、LINC02611/miR-139-5p/MS4A6A 和 PCED1B-AS1/miR-433-3p/MS4A6A 可能在 GBM 的发病机制中发挥重要作用。MS4A6A 在 GBM 中上调，并与患者的生存时间较短密切相关。我们还发现 MS4A6A 的表达与与肿瘤相关的巨噬细胞相关的基因呈正相关，这些基因诱导巨噬细胞浸润和免疫抑制。功能富集分析表明，DElncRNA 主要参与神经活性配体-受体相互作用、钙/MAPK 信号通路、核糖体、GABA 能/血清素能/谷氨酸能突触和免疫系统过程。此外，与 MS4A6A 相关的基因参与免疫和炎症相关的生物学过程。我们的研究结果为理解 GBM 中的 ceRNA 调控提供了新的见解，并确定了新型预后生物标志物或治疗靶点。

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