自噬相关基因在类风湿关节炎滑膜组织的表达及调控机制  

Expression and Regulatory Mechanism of Autophagy-related Genes in Synovial Tissues of Patients with Rheumatoid Arthritis

作　　者：陈雪芹 李灵兰 付国涛 韩莉欣 毋瑞朋 熊咏民[3] 史传道 刘启玲 张荣强 CHEN Xueqin;LI Linglan;FU Guotao;HAN Lixin;WU Ruipeng;XIONG Yongmin;SHI Chuandao;LIU Qiling;ZHANG Rongqiang(Department of Epidemiology and Health Statistics,School of Public Health,Shaanxi University of Chinese Medicine,Xianyang,Shaanxi 712046,China;Disease Control Division,Shaanxi Provincial Health Commission,Xi’an 710003,China;Institute of Endemic Diseases,School of Public Health,Xi’an Jiaotong University,Xi’an 710061,China;Department of Public Health and Preventive Medicine,Xizang Minzu University,Xianyang,Shaanxi 712082,China)

机构地区：[1]陕西中医药大学公共卫生学院流行病与卫生统计学教研室,陕西咸阳712046 [2]陕西省卫生健康委员会疾病控制处,西安710003 [3]西安交通大学公共卫生学院地方病研究所,西安710061 [4]西藏民族大学医学公共卫生与预防医学教研室,陕西咸阳712082

出　　处：《中国医学科学院学报》2022年第6期950-960,共11页Acta Academiae Medicinae Sinicae

基　　金：陕西省重点研发计划项目(2020SF-076);陕西省教育厅重点科学研究计划项目(19JS015);陕西中医药大学慢性非传染性疾病病因及机制研究创新团队(132041933);中国富硒产业研究院富硒产业全产业链专项研发计划项目(2020FXZX05-01)。

摘　　要：目的研究自噬相关基因(ATG)在类风湿关节炎(RA)中的表达调控和自噬机制。方法从GSE55235和GSE55457中鉴定出RA的差异表达基因(DEG),结合人类自噬数据库,筛选出差异表达自噬相关基因(DE-ATG)。利用STRING 11.0和GeneMANIA数据库建立蛋白互作网络。此外,NetworkAnalyst和Cytoscape建立转录因子-基因-miRNA共表达网络。最后,受试者工作特征曲线分析和DrugBank鉴定预测生物标志物的效能和靶向药物的性能。GraphPad prism 8.2.1和R 4.0.3用于统计分析和图形制作。结果485个DEG在T细胞激活、激素调节、破骨细胞分化、RA和趋化因子等信号通路富集。11个DE-ATG通过hsa-mir-155-5p、RUNX1、TP53和SOX2等调控RA滑膜组织的表达,与四氯二苯二氧芑、二氧化硅有较强的环境因子调控关系。受试者工作特征曲线分析确定了具有良好敏感性和特异性的基因,如MYC、MAPK8、CDKN1A和TNFSF10,可用于区分某些表型,这可能是RA的新型生物标志物。结论DE-ATG在RA中表达下调可能会促进软骨细胞凋亡和分解,新型生物标志物的确立为诊断和治疗RA提供了新思路和方法,转录因子-基因-miRNA网络的建立为解析滑膜炎症和关节软骨破坏提供直接证据。Objective To investigate the expression regulation of autophagy-related genes(ATG)and the mechanism of autophagy in rheumatoid arthritis(RA).Methods The differentially expressed genes(DEG)of RA were identified from GSE55235 and GSE55457,on the basis of which the differentially expressed autophagy-related genes(DE-ATG)were selected from the Human Autophagy Database.STRING 11.0 and GeneMANIA were used to establish protein-protein interaction networks.Further,the transcription factor-gene-miRNA co-expression network was established via NetworkAnalyst and Cytoscape.Finally,receiver operating characteristic(ROC)curve and DrugBank were employed to evaluate the efficacy of the predicted biomarkers and the performance of drugs targeting DE-ATG.GraphPad Prism 8.2.1 and R 4.0.3 were used for statistical analysis and graphics.Results A total of 485 DEG were enriched in signaling pathways such as T cell activation,hormone regulation,osteoclast differentiation,RA,and chemokines.Eleven DE-ATG regulated the expression of RUNX1,TP53,SOX2,and hsa-mir-155-5 p in synovial tissues of RA patients and were involved in the response to environmental factors such as 2,3,7,8-tetrachlorodibenzodioxin and silicon dioxide.The ROC curve analysis identified the DE-ATG with good sensitivity and specificity,such as MYC,MAPK8,CDKN1 A,and TNFSF10,which can be used to distinguish certain phenotypes and serve as novel biomarkers for RA.Conclusions In RA,down-regulated DE-ATG expression may promote apoptosis and lysis of chondrocytes.The identified novel biomarkers provides new ideas and methods for diagnosing and treating RA.The establishment of transcription factor-miRNA-gene co-expression network provides direct evidence for dissecting synovial inflammation and articular cartilage destruction.

关 键 词：类风湿关节炎 自噬 转录因子 MIRNA 

分 类 号：R684.3[医药卫生—骨科学]