间充质细胞源性骨肉瘤中关键分子标志物鉴定及药物敏感性分析  

Identification and drug sensitivity analysis of key molecular markers in mesenchymal cell-derived osteosarcoma

作　　者：张昊军 李泓毅 张辉[4] 陈浩然 张力中 耿杰 侯传东 于琦 贺培凤 贾金鹏 卢学春 Zhang Haojun;Li Hongyi;Zhang Hui;Chen Haoran;Zhang Lizhong;Geng Jie;Hou Chuandong;Yu Qi;He Peifeng;Jia Jinpeng;Lu Xuechun(School of Basic Medicine,Shanxi Medical University,Taiyuan 030600,Shanxi Province,China;Department of Hematology,Second Medical Center,Chinese PLA General Hospital,National Center for Clinical Research of Geriatric Diseases,Beijing 100853,China;Chinese PLA Medical College,Beijing 100853,China;Academy of Medical Sciences,Shanxi Medical University,Taiyuan 030600,Shanxi Province,China;School of Management,Shanxi Medical University,Taiyuan 030600,Shanxi Province,China;Department of Orthopedic Medicine,Fourth Medical Center of Chinese PLA General Hospital,Beijing 100853,China)

机构地区：[1]山西医科大学基础医学院,山西省太原市030600 [2]中国人民解放军总医院第二医学中心血液病科,国家老年疾病临床医学研究中心,北京市100853 [3]解放军医学院,北京市100853 [4]山西医科大学医学科学院,山西省太原市030600 [5]山西医科大学管理学院,山西省太原市030600 [6]中国人民解放军总医院第四医学中心骨科医学部,北京市100853

出　　处：《中国组织工程研究》2025年第7期1448-1456,共9页Chinese Journal of Tissue Engineering Research

基　　金：国家重点研发计划(2020YFC2002706-2),项目负责人:卢学春;山西省健康医疗大数据智能平台关键技术研究(201903D311011),项目负责人:于琦;军队后勤自主科研课题(2022HQZZ06),项目负责人:卢学春。

摘　　要：背景:骨肉瘤发病机制复杂,预后较差,随着医疗技术的发展,其5年生存率有所改善,但仍未取得实质性进展。目的:筛选骨肉瘤中关键分子标志物,分析其与骨肉瘤治疗药物之间的关系,并从分子水平探讨骨肉瘤可能的疾病机制。方法:从基因表达谱数据库中获取GSE99671和GSE28425(miRNA),对GSE99671进行差异表达基因分析和加权基因共表达网络分析(WGCNA)。利用基因本体学(GO)和京都基因与基因组百科全书(KEGG)分别对差异表达基因和与疾病正相关性最高的模块基因进行功能富集分析。将上述模块基因与差异表达基因取交集作为关键基因,构建蛋白质相互作用网络,使用CytoScape软件对关键基因进行相关性分析,筛选枢纽基因(Hub基因)。使用GSE28425数据集对Hub基因进行外部验证,同时对Hub基因进行文本验证。使用CellMiner数据库对Hub基因进行药物敏感性分析,依据关联系数的绝对值|R|>0.3,P<0.05作为阈值进行筛选。结果与结论:(1)差异表达分析获得529个差异表达基因,其中177个表达上调,352个表达下调;WGCNA分析共得到592个与骨肉瘤相关性最高的基因;(2)GO富集结果显示骨肉瘤的发生发展可能与细胞外基质、骨细胞的分化与发育、人体的免疫调控、胶原蛋白的合成与分解相关;KEGG富集结果显示PI3K-Akt信号通路、焦点黏附信号通路、免疫应答等参与骨肉瘤疾病的发生;(3)交集结果显示,共获得59个关键基因,经蛋白质相互作用网络分析,筛选得到8个Hub基因,分别为LUM、PLOD1、PLOD2、MMP14、COL11A1、THBS2、LEPRE1、TGFB1,且均为表达上调;(4)外部验证发现调控Hub基因的miRNA明显下调,其中hsa-miR-144-3p和hsa-miR-150-5p的下调最为显著;文本验证结果显示Hub基因的表达与既往研究基本一致;(5)药物敏感性分析发现甲氨蝶呤、异环磷酰胺、帕博西尼的活性与PLOD1、PLOD2、MMP14的mRNA表达呈负相关关系;而唑来膦酸、�BACKGROUND:Osteosarcoma has a complex pathogenesis and a poor prognosis.While advancements in medical technology have led to some improvements in the 5-year survival rate,substantial progress in its treatment has not yet been achieved.OBJECTIVE:To screen key molecular markers in osteosarcoma,analyze their relationship with osteosarcoma treatment drugs,and explore the potential disease mechanisms of osteosarcoma at the molecular level.METHODS:GSE99671 and GSE284259(miRNA)datasets were obtained from the Gene Expression Omnibus database.Differential gene expression analysis and Weighted Gene Co-expression Network Analysis(WGCNA)on GSE99671 were performed.Functional enrichment analysis was conducted using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes separately for the differentially expressed genes and the module genes with the highest positive correlation to the disease.The intersection of these module genes and differentially expressed genes was taken as key genes.A Protein-Protein Interaction network was constructed,and correlation analysis on the key genes was performed using CytoScape software,and hub genes were identified.Hub genes were externally validated using the GSE28425 dataset and text validation was conducted.The drug sensitivity of hub genes was analyzed using the CellMiner database,with a threshold of absolute value of correlation coefficient|R|>0.3 and P<0.05.RESULTS AND CONCLUSION:(1)Differential gene expression analysis identified 529 differentially expressed genes,comprising 177 upregulated and 352downregulated genes.WGCNA analysis yielded a total of 592 genes with the highest correlation to osteosarcoma.(2)Gene Ontology enrichment results indicated that the development of osteosarcoma may be associated with extracellular matrix,bone cell differentiation and development,human immune regulation,and collagen synthesis and degradation.Kyoto Encyclopedia of Genes and Genomes enrichment results showed the involvement of pathways such as PI3K-Akt signaling pathway,focal adhesion signaling p

关 键 词：骨肉瘤 分子标志物 信号通路 药物预测 WGCNA 药物敏感性 生物信息学 

分 类 号：R459.9[医药卫生—治疗学] R318[医药卫生—临床医学] R739.9