摘要
目的探讨泛素样含植物同源结构域和环指结构域蛋白1(UHRF1)基因在软组织肉瘤(soft tissue sarcoma,STS)中的表达模式和分子功能及其与STS临床特征、预后的相关性。方法从TCGA选取263例STS组织的RNA数据及相关临床数据。采用Wilcoxon秩和检验分析两组数据的相关性;Spearman相关分析STS数据中与UHRF1表达呈正相关和负相关的前35个共表达基因,ggplot2统计软件包显示共表达基因热图,Pearson相关分析UHRF1的表达与热图中前10个基因表达之间的相关性;采用deseq2软件包对STS中不同的UHRF1基因表达组进行分析,ggplot2软件包绘制火山图,GO和KEGG富集分析差异表达基因(DEGs)及蛋白产物功能,ggplot2和cluster Profiler软件包进行可视化和统计分析;采用STRING web建立DEGs的PPI网络,采用Cytoscape中CytoHubba的MCC算法对枢纽基因进行分析。结果在STS中,UHRF1基因与其组织学类型(脂肪肉瘤22.2%、滑膜肉瘤3.8%、平滑肌肉瘤40.7%、恶性周围神经鞘瘤3.8%、黏液纤维肉瘤9.6%、多形性肉瘤19.9%,P=0.001)、肿瘤坏死(无坏死38.8%、局灶性坏死20.8%、中度坏死33.8%、广泛坏死6.6%,P=0.010)、肿瘤转移(未转移67%、转移33%,P<0.001)有显著的相关性。在不同的临床亚组(年龄、性别、组织学类型、残余肿瘤、肿瘤坏死、肿瘤深度、边缘状态、肿瘤多灶性、放射治疗),高表达UHRF1可导致总生存(OS)、疾病特异性生存(DSS)和无进展间期(PFI)缩短的不良预后;以下5个亚组在以上3个预后因素中同时缩短,即残余肿瘤为R0和R1期,肿瘤坏死为广泛性、局灶性和中度,肿瘤深度为深,边缘状态呈现阳性,肿瘤无多灶性。对和UHRF1表达相关的35个共表达基因中的前10个进行分析发现,正相关基因为PAGE5、LINC01425、LCEP3、SERPINB7、AC074031.1、LCE3A、LCE2A、PAGE2B、MYF5、和AC037486.1(P<0.05);负相关基因为CDH19、CSN1S1、TAC3、AC103563.7、SAA1、CHST8、PRLHR、MIR202HG、IGHV1-24、ART4(P<0.05)。获得阈值为|log2 fold-change(FC)|>1.0且调整P<0.05的UHRF1在STS中的DEGs 3029个,其中上调基因1228个,下调基因1801个;用GO富集分析初级生物学过程(BP)、原始的细胞成分(CC)及原始的分子功能(MF),用KEGG富集分析信号通路。获得阈值为log2 fold-change(FC)|>2.0调整后P值<0.05的DEGs 343个,其中上调基因133个,下调基因210个;分析其前10个枢纽基因,前3个枢纽基因分别是GCG、SST和SHH。结论UHRF1与STS组织学类型、肿瘤坏死、转移及OS、DSS、PFI事件有显著相关性,其分子功能在共基因表达模型中,正负相关基因涉及多个生物学过程,其差异表达基因及蛋白产物相互作用的网络涉及疾病发生发展机制,为STS的深入研究提供了新思路。
Objective To explore the expression pattern and molecular function of ubiquitin-like containing PHD and RING finger domains 1(UHRF1)gene in soft tissue sarcoma(STS),as well as its correlation with clinical characteristics and prognosis of STS.Methods RNA data and related clinical data of 263 STS tissues were obtained from Cancer Genome Atlas(TCGA).Wilcoxon rank-sum test was used to analyze correlation between two groups of data;Spearman correlation coefficient analyzed the top 35 co-expressed genes positively and negatively correlated with UHRF1 expression in STS database,ggplot2 statistical package displayed co-expressed gene heatmap,Pearson correlation coefficient showed correlation between UHRF1 expression and expression of the top 10 genes in the heatmap;different UHRF1 gene expression groups in STS were analyzed using DESeq2 package,ggplot2 package was used to draw volcano plots,gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyzed differentially expressed genes(DEGs)and protein functions,ggplot2 package for visualization,and cluster Profiler package for statistical analysis;STRING web was used to establish PPI network of DEGs,and the MCC algorithm in CytoHubba of Cytoscape was used to analyze hub genes.Results In STS,UHRF1 gene was significantly correlated with its histological type(liposarcoma 22.2%,synovial sarcoma 3.8%,leiomyosarcoma 40.7%,malignant peripheral nerve sheath tumor 3.8%,myxofibrosarcoma 9.6%,pleomorphic sarcoma 19.9%,P=0.001),tumor necrosis(none 38.8%,focal necrosis 20.8%,moderate necrosis 33.8%,extensive necrosis 6.6%,P=0.010),and tumor metastasis(no metastasis 67%,metastasis 33%,P<0.001).In different clinical subgroups(age,gender,histological type,residual tumor,tumor necrosis,tumor depth,margin status,tumor multifocality,radiotherapy),high expression of UHRF1 led to poor prognosis of overall survival(OS),disease-specific survival(DSS),and progression-free interval(PFI);Three prognostic factors above were simultaneously shortened in the following five subgroups:namely residual tumor R0 and R1,tumor necrosis extensive,focal and moderate,tumor depth deep,positive margin status,tumor without multifocality.Analysis of the top 10 co-expressed genes associated with UHRF1 expression revealed that the associated positive genes were PAGE5,LINC01425,LCEP3,SERPINB7,AC074031.1,LCE3A,LCE2A,PAGE2B,MYF5,and AC037486.1(P<0.05);the associated negative genes were CDH19,CSN1S1,TAC3,AC103563.7,SAA1,CHST8,PRLHR,MIR202HG,IGHV1-24,and ART4(P<0.05).A total of 3029 DEGs of UHRF1 in STS were obtained with a threshold of|log2 fold-change(FC)|>1.0 and adjusted P value<0.05,in which 1228 genes were up-regulated and 1801 genes were down-regulated;GO enrichment analyed primary biological processes(BP),original cellular components(CC),and original molecular functions(MF),and KEGG enrichment analyed signaling pathways.A total of 343 DEGs including 133 up-regulated genes and 210 down-regulated genes,were obtained with a threshold of|log2 fold-change(FC)|>2.0 and adjusted P value<0.05.The top 10 hub genes were analyzed.The top 3 hub genes were GCG,SST and SHH,respectively.Conclusion UHRF1 is significantly correlated with histological type,tumor necrosis,metastasis,OS,DSS,and PFI events in STS.In co expressed genes model and molecular functions of related positive and negative genes involved in multiple biological processes;The network of differentially expressed genes and protein product interactions involved in mechanisms of occurrence and development of the disease,and provided new ideas for in-depth researches on STS.
作者
严毅进
王欢
丁一帆
徐浩然
胡伟华
方煌
YAN Yijin;WANG Huan;DING Yifan;XU Haoran;HU Weihua;FANG Huang(Department of Orthopedics,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China)
出处
《临床外科杂志》
2025年第7期735-740,共6页
Journal of Clinical Surgery
基金
国家自然科学基金资助项目(81271347)。
关键词
泛素样含植物同源结构域和环指结构域蛋白1
软组织肉瘤
临床特征
共表达基因
差异表达基因
分子功能
ubiquitin-like containing PHD and RING finger domains 1
soft tissue sarcoma
clinical characteristics
co-expressed genes
differentially expressed genes
molecular function
