摘要
目的 基于空间转录组、单细胞转录组和RNA转录组测序数据探讨BICD1基因促进脑胶质瘤恶性进展的分子机制.方法 基于空间转录组公共数据集分析BICD1基因在正常脑组织(样本"248_C")和胶质母细胞瘤组织(样本"275_T")中的空间分布特征.采用R语言软件包分析中国脑胶质瘤基因组图谱(CGGA)数据库中单细胞测序数据(来源于14例患者的6 148个细胞),明确BICD1基因在胶质瘤不同细胞类型中的表达差异.基于CGGA数据库中693例脑胶质瘤患者的RNA测序数据,采用京都基因与基因组百科全书(KEGG)通路富集分析及基因本体论分析BICD1基因相关基因的生物学功能.结果 BICD1基因在正常脑组织中表达广泛,在胶质母细胞瘤组织中特异性地表达于肿瘤干细胞与肿瘤细胞的分界处.根据单细胞测序数据进行的细胞分群分析表明,BICD1基因主要在星形胶质细胞中高表达.在Neftel分型中,BICD1基因高表达细胞主要分布在星形胶质细胞样细胞群和神经前体样细胞群中.BICD1基因表达水平相关差异基因的KEGG通路富集分析显示,BICD1基因高表达与细胞衰老(P=0.003)、癌症中的蛋白聚糖(P=0.004)等癌症相关生物学功能的聚集相关,与肌动蛋白细胞骨架的调节(P=0.010)等胞内运输过程的功能聚集相关;BICD1基因低表达与核糖体相关功能(P<0.001)及氧化磷酸化(P<0.001)等生物学过程的聚集相关.BICD1基因表达水平相关差异基因的生物学功能聚类分析显示,与BICD1基因表达水平相关性较强的生物学功能有细胞质翻译(P<0.001)、核糖体亚单位装配(P=0.001)、染色体分离调控(P=0.004)及染色体分离(P=0.004)等.BICD1基因的表达水平与多泛素修饰依赖性蛋白结合(P=0.046)、泛素-泛素连接酶活性(P=0.033)、蛋白质解聚负调控(P=0.010)、单泛素化蛋白质去泛素化(P=0.026)、肌动蛋白丝加帽(P=0.007)、肌动蛋白丝解聚(P=0.013)等生物学过程相关.结论 BICD1蛋白可能在脑胶质瘤前体肿瘤细胞中参与蛋白泛素化降解及细胞骨架相关的胞内运输,调控细胞衰老和细胞分裂等生物学过程,在这些细胞的恶性转变过程中起到关键作用.
ObjectiveTo investigate the molecular mechanism of BICD1 gene promoting malignant progression of brain glioma based on spatial transcriptomic,single-cell sequencing data and RNA transcriptomic.MethodsPublic dataset of spatial transcriptome was employed to analyze the spatial distribution characteristics of BICD1 in normal brain tissues(sample:"248_C")and glioblastoma tissues(sample:"275_T").Single-cell sequencing data(from 6148 cells of 14 patients)in Chinese Glioma Genome Atlas(CGGA)database were adopted to decipher the expression difference of BICD1 in different glioma cell types by R-language software.The biological functions of BICD1-related genes were analyzed based on RNA sequencing data in CGGA database(n=693)via the Kyoto Encyclopedia of Genes and Genomes(KEGG)and the Gene Ontology(GO)analyses.ResultsBICD1 was expressed in a wide range in normal brain tissues and specifically expressed at the boundary between glioma stem cells and tumor cells in glioblastoma tissues.Cell subtyping analyses based on single-cell sequencing data showed that BICD1 was highly expressed in astrocytes.In the Neftel subtyping system,cells with BICD1 highly expressed were mainly distributed in astrocytes-like cells and neural progenitor-like cells clusters.KEGG pathway analyses of BICD1-related differential genes showed that high expression of BICD1 was associated with enrichments of tumor-related biological functions such as cellular senescence(P=0.003),proteoglycans in cancer(P=0.004),and enrichments of intracellular transport processes such as actin cytoskeleton regulation(P=0.010).Low expression of BICD1 was associated with enrichments of ribosome-related functions(P<0.001)and biological processes such as oxidative phosphorylation(P<0.001).GO analyses of BICD1-related differential genes showed that cytoplasmic translation(P<0.001),ribosome small subunit assembly(P=0.001),regulation of chromosome separation(P=0.004)and chromosome separation(P=0.004)were significantly correlated with BICD1 expression levels.The expression level of BICD1 was significantly correlated with biological processes such as polyubiquitin modified-dependent protein binding(P=0.046),ubiquitin-ubiquitin ligase activity(P=0.033),negative regulation of protein depolymerization(P=0.010),monoubiquitinated protein deubiquitination(P=0.026),actin filament capping(P=0.007)and actin filament depolymerization(P=0.013).ConclusionBICD1 might be involved in protein ubiquitination degradation and cytoskeleton-related intracellular transport in precursor glioma cells,and plays a critical role in the malignant transformation of those cells by regulating biological processes such as cell senescence and cell division.
作者
胡慧敏
刘博涵
彭大钊
陈彦坤
李阳芳
Hu Huimin;Liu Bohan;Peng Dazhao;Chen Yankun;Li Yangfang(Beijing Neurosurgical Institute,Beijing 100070,China)
出处
《中华神经外科杂志》
CSCD
北大核心
2024年第2期190-196,共7页
Chinese Journal of Neurosurgery
基金
国家自然科学基金(81972816)
国家蛋白质科学基础设施(北京)北大分中心开放课题(KF-202301)
北京市科技新星计划(20220484029)。
作者简介
通信作者:李阳芳,Email:cclslyf@163.com。
