1) 首都医科大学附属北京天坛医院神经外科,北京 100070;2) 首都医科大学,北京市神经外科研究所,北京 100070
国家自然科学基金(81974387,82003023,82373451),北京市自然海淀联合基金-海淀原始创新联合基金(L222015)和北京市属医学科研院所公益发展改革试点项目(京医研2023-2)资助。
1) Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China;2) Beijing Neurosurgical Institute, Capital Medical University, Beijing 100070, China
This work was supported by grants from The National Natural Science Foundation of China (81974387, 82003023, 82373451), Beijing Municipal Natural Science Foundation (L222015), and Public Welfare Development and Reform Pilot Project of Beijing Medical Research Institute (JYY 2023-2).
目的 本文旨在确定NF2表达阴性脑膜瘤中潜在的miRNA-mRNA轴,研究它们的靶向关系,并确定它们的生物学功能。方法 从基因表达数据库(GEO)下载包含与NF2阴性脑膜瘤相关数据的GSE17792数据集。使用R软件中的limma包确定差异表达的miRNA(DeMiRNAs)。应用miRWalk 2.0数据库获取DeMiRNAs的靶基因。利用相互作用基因检索工具(STRING)数据库构建蛋白质相互作用(PPI)网络,并通过Cytoscape软件确定核心基因。对筛选出的miRNA进一步验证其表达和生物学作用。结果 在NF2阴性脑膜瘤肿瘤样本与蛛网膜组织对照组比较中发现了86个差异miRNA,其中包括52个上调的miRNAs和34个下调的miRNAs。在这些差异miRNA中鉴定出与274个靶基因相关的14个miRNAs,并基于这些数据构建miRNA-靶基因网络。通过cytoHubba分析显示,在PPI网络中有两个miRNAs(hsa-miR-650和hsa-miR-623)位于前20个关键核心基因之中。进一步的定量逆转录PCR(qRT-PCR)实验证实,相对于正常脑组织,hsa-miR-650在NF2阴性脑膜瘤中的表达显著增高。下调hsa-miR-650抑制了NF2阴性脑膜瘤细胞的增殖并诱导细胞凋亡。最后,确定RAC1是hsa-miR-650的靶基因。结论 Hsa-miR-650作为肿瘤促进剂,可能作为治疗NF2阴性脑膜瘤患者的治疗靶点。
Objective This study aimed to identify a potential miRNA-mRNA axis in neurofibromatosis type 2 (NF2)-negative meningiomas, investigate their target relationships, and determine their biological functions.Methods The GSE17792 dataset, which contains data related to NF2-negative meningiomas, was downloaded from the Gene Expression Omnibus (GEO) database. The limma package of R software was used to determine the differentially expressed miRNAs (DeMiRNAs). The miRWalk 2.0 database was applied to obtain the target genes of DeMiRNAs. The Search Tool for the Retrieval of Interacting Genes (STRING) database was utilized to build protein-protein interaction (PPI) networks, and hub genes were identified via Cytoscape software. The expression and biological roles of the screened miRNAs were further validated.Results Altogether, 86 DeMiRNAs, consisting of 52 upregulated and 34 downregulated miRNAs, were found in NF2-negative meningioma tumor samples compared with arachnoid tissue controls. Fourteen miRNAs associated with 274 target genes were identified among these DeMiRNAs, and miRNA-target gene networks were constructed based on these data. Analysis with cytoHubba showed that two miRNAs (hsa-miR-650 and hsa-miR-623) were among the top 20 key hub genes in the PPI network. Further qRT-PCR experimental verification suggested that the expression of hsa-miR-650 was significantly higher in NF2-negative meningiomas than in normal brain tissues. Downregulation of hsa-miR-650 inhibited the proliferation and induced the apoptosis of NF2-negative meningioma cells. Finally, RAC1 was identified as a target of hsa-miR-650.Conclusion Hsa-miR-650 acts as a tumor promoter and might function as a therapeutic target for patients with NF2-negative meningiomas.
张超,李朋,王博,汪颖,刘丕楠. Hsa-miR-650通过靶向RAC1抑制NF2阴性脑膜瘤的生长[J].生物化学与生物物理进展,2024,51(7):1687-1696
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