解放军医学杂志2025，Vol.50Issue(12)：1549-1556,8.DOI:10.11855/j.issn.0577-7402.0880.2025.1028
基于转录组测序探索IDH1突变促进胶质瘤血管生成的机制
Exploring the mechanism of IDH1 mutation in promoting glioma angiogenesis through transcriptome sequencing
摘要
Abstract
Objective To investigate the impact of isocitrate dehydrogenase 1(IDH1)mutation on angiogenesis in glioma and to screen and validate the involved differentially expressed genes.Methods Pathological specimens from 198 glioma patients treated at the General Hospital of Ningxia Medical University were collected.Immunohistochemistry(IHC)was used to assess the positive expression rates of IDH1 mutation and angiogenesis-related factors CD34 and vascular endothelial growth factor(VEGF),qPCR was used to measure the expression levels of angiogenesis-related regulators[e.g.,VEGFA and SRY-box transcription factor 18(SOX18)]in two groups.Doxycycline-induced IDH1-mutant U87 glioma cells served as IDH1-mutation group,and uninduced U87 cells served as control group.RNA sequencing(RNA-seq)was performed to compare gene expression profiles between two groups.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were conducted to evaluate differentially expressed genes and their effects on related signaling pathways.Western blotting and qPCR were used to analyze expression differences in angiogenesis-related factors such as ETS proto-oncogene 1(ETS1)and VEGFC.Results IHC detected IDH1 mutation in 102(51.5%)of the 198 glioma cases,which was associated with significantly increased CD34 and VEGF expression(P<0.05).Similarly,qPCR results indicated that,in U87 cells,IDH1 mutation promoted the upregulation of angiogenesis-related genes(VEGFA,SOX18,bone morphogenetic protein 6(BMP6),ephrin-A2(EFNA2),and Wnt family member 1(WNT1)]while concurrently downregulating Rap guanine nucleotide exchange factor 4(RAPGEF4)in contrast to control group(P<0.05).Transcriptomic analysis revealed that IDH1 mutation influences angiogenic pathways through epigenetic regulation.Western blotting and qPCR confirmed that U87 cells in IDH1-mutation group exhibited significant concurrent upregulation at both the mRNA and protein levels of key angiogenesis-related factors such as ETS1,GATA-binding protein 2/3(GATA2/3),VEGFC,and platelet-derived growth factor receptor alpha(PDGFRA)compared with control group(P<0.05).Conclusions IDH1 mutation markedly upregulates the transcription and protein expression of angiogenesis-related genes(such as ETS1,VEGFC,BMP6,and SOX18)in glioma cells through epigenetic regulation,thereby promoting angiogenesis.This process likely involves the coordinated actions of endothelial cells,fibroblasts,and the extracellular matrix within the tumor microenvironment.关键词
IDH1突变/神经胶质瘤/病理性新生血管化/转录组测序Key words
IDH1 mutations/glioma/neovascularization,pathologic/transcriptome sequencing分类
医药卫生引用本文复制引用
He Yu-Hong,Yang Ji-Hua,Li Yuan-Feng,Ma Bo,Yu Tian,Cao Xiang-Mei,Hou Shao-Zhang..基于转录组测序探索IDH1突变促进胶质瘤血管生成的机制[J].解放军医学杂志,2025,50(12):1549-1556,8.基金项目
This work was supported by the Key Research and Development Program of Ningxia(2023BEG02009),and the National Natural Science Foundation of China(82260509) 宁夏重点研发项目(2023BEG02009) （2023BEG02009）
国家自然科学基金(82260509) （82260509）
