鉴定和验证 CDKN1A 和 HDAC1 作为慢性阻塞性肺疾病衰老相关的枢纽基因。
Identification and Validation of CDKN1A and HDAC1 as Senescence-Related Hub Genes in Chronic Obstructive Pulmonary Disease.
机构信息
Department of Pulmonary and Critical Care Medicine, Qilu Hospital of Shandong University, Shandong Key Laboratory of Infectious Respiratory Diseases, Jinan, People's Republic of China.
Department of Gerontology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, People's Republic of China.
出版信息
Int J Chron Obstruct Pulmon Dis. 2022 Aug 10;17:1811-1825. doi: 10.2147/COPD.S374684. eCollection 2022.
PURPOSE
Cellular senescence participates in the occurrence and development of chronic obstructive pulmonary disease (COPD). This study aimed to identify senescence-related hub genes and explore effective diagnostic markers and therapeutic targets for COPD.
METHODS
The microarray data from the GSE38974 dataset was downloaded from the Gene Expression Omnibus (GEO) database. The overlapping genes between genes from the GSE38974 dataset and CellAge database were considered differentially expressed senescence-related genes (DESRGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using R software. Protein-protein interaction (PPI), miRNA-mRNA network, and competitive endogenous RNA (ceRNA) network were constructed and visualized by Cytoscape software. GSE100281 and GSE103174 datasets were employed to validate the expression and diagnostic value of hub genes. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to measure the mRNA levels of hub genes in peripheral blood mononuclear cells (PBMCs) from COPD and control samples.
RESULTS
A total of 23 DESRGs were identified between COPD samples and healthy controls. Enrichment analysis revealed that DESRGs were mainly related to apoptosis and senescence. Moreover, four hub genes and two key clusters were acquired by Cytohubba and MCODE plugin, respectively. CDKN1A and HDAC1 were verified as final hub genes based on GSE100281 and GSE103174 datasets validation. The mRNA expression level of CDKN1A was negatively related to forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC), and HDAC1 expression had the opposite correlation. Finally, an HDAC1-based ceRNA network, including 6 miRNAs and 11 lncRNAs, was constructed.
CONCLUSION
We identified two senescence-related hub genes, CDKN1A and HDAC1, which may be effective biomarkers for COPD diagnosis and treatment. An HDAC1-related ceRNA network was constructed to clarify the role of senescence in COPD pathogenesis.
目的
细胞衰老参与慢性阻塞性肺疾病（COPD）的发生和发展。本研究旨在鉴定衰老相关的枢纽基因，并探索 COPD 的有效诊断标志物和治疗靶点。
方法
从基因表达综合数据库（GEO）中下载 GSE38974 数据集的微阵列数据。将 GSE38974 数据集和 CellAge 数据库中的基因重叠的基因视为差异表达的衰老相关基因（DESRGs）。使用 R 软件进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）通路富集分析。通过 Cytoscape 软件构建和可视化蛋白质-蛋白质相互作用（PPI）、miRNA-mRNA 网络和竞争内源性 RNA（ceRNA）网络。使用 GSE100281 和 GSE103174 数据集验证枢纽基因的表达和诊断价值。使用逆转录定量聚合酶链反应（RT-qPCR）测量 COPD 和对照样本外周血单个核细胞（PBMC）中枢纽基因的 mRNA 水平。
结果
在 COPD 样本和健康对照之间共鉴定出 23 个 DESRGs。富集分析表明，DESRGs 主要与细胞凋亡和衰老有关。此外，通过 Cytohubba 和 MCODE 插件分别获得了 4 个枢纽基因和 2 个关键聚类。基于 GSE100281 和 GSE103174 数据集的验证，CDKN1A 和 HDAC1 被验证为最终的枢纽基因。CDKN1A 的 mRNA 表达水平与 1 秒用力呼气量/用力肺活量（FEV1/FVC）呈负相关，HDAC1 的表达则呈正相关。最后，构建了一个基于 HDAC1 的 ceRNA 网络，包括 6 个 miRNA 和 11 个 lncRNA。
结论
我们鉴定了两个衰老相关的枢纽基因，CDKN1A 和 HDAC1，它们可能是 COPD 诊断和治疗的有效生物标志物。构建了一个基于 HDAC1 的 ceRNA 网络，以阐明衰老在 COPD 发病机制中的作用。
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