Feng Xueyan, Dong Hui, Li Beibei, Yu Liang, Zhu Jinyuan, Lou Caili, Zhang Jin
Clinical medical school, Ningxia Medical University, Yinchuan, China.
Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, China.
Front Genet. 2023 Jan 30;14:1050783. doi: 10.3389/fgene.2023.1050783. eCollection 2023.
The pathogenesis of Chronic Obstructive Pulmonary Disease (COPD) is implicated in airway inflammation, oxidative stress, protease/anti-protease and emphysema. Abnormally expressed non-coding RNAs (ncRNAs) play a vital role in regulation of COPD occurrence and progression. The regulatory mechanisms of the circRNA/lncRNA-miRNA-mRNA (competing endogenous RNA, ceRNA) networks might facilitate our cognition of RNA interactions in COPD. This study aimed to identified novel RNA transcripts and constructed the potential ceRNA networks of COPD patients. Total transcriptome sequencing of the tissues from patients with COPD (COPD) ( = 7) and non-COPD control subjects (Normal) ( = 6) was performed, and the expression profiles of differentially expressed genes (DEGs), including mRNAs, lncRNAs, circRNAs, and miRNAs, were analyzed. The ceRNA network was established based on the miRcode and miRanda databases. Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), Gene Set Enrichment Analysis (GSEA), and Gene set variation analysis (GSVA) were implemented for functional enrichment analysis of DEGs. Finally, CIBERSORTx was extracted to analyze the relevance between hub genes and various immune cells.The Starbase and JASPAR databases were used to construct hub-RNA binding proteins (RBPs) and lncRNA-transcription factor (TF) interaction networks. A total of 1,796 mRNAs, 2,207 lncRNAs, and 11 miRNAs showed differentially expression between the lung tissue samples from the normal and COPD groups. Based on these DEGs, lncRNA/circRNA-miRNA-mRNA ceRNA networks were constructed respectively. In addition, ten hub genes were identified. Among them, RPS11, RPL32, RPL5, and RPL27A were associated with the proliferation, differentiation, and apoptosis of the lung tissue. The biological function revealed that TNF-α via NF-kB and IL6/JAK/STAT3 signaling pathways were involved in COPD. Our research constructed the lncRNA/circRNA-miRNA-mRNA ceRNA networks, filtrated ten hub genes may regulate the TNF-α/NF-κB, IL6/JAK/STAT3 signally pathways, which indirectly elucidated the post-transcriptional regulation mechanism of COPD and lay the foundation for excavating the novel targets of diagnosis and treatment in COPD.
慢性阻塞性肺疾病（COPD）的发病机制与气道炎症、氧化应激、蛋白酶/抗蛋白酶及肺气肿有关。异常表达的非编码RNA（ncRNAs）在COPD的发生和发展调控中起着至关重要的作用。环状RNA/长链非编码RNA-微小RNA-信使RNA（竞争性内源RNA，ceRNA）网络的调控机制可能有助于我们认识COPD中的RNA相互作用。本研究旨在鉴定新的RNA转录本并构建COPD患者潜在的ceRNA网络。对COPD患者（n = 7）和非COPD对照受试者（正常组，n = 6）的组织进行全转录组测序，并分析差异表达基因（DEGs）的表达谱，包括信使RNA、长链非编码RNA、环状RNA和微小RNA。基于miRcode和miRanda数据库建立ceRNA网络。对DEGs进行京都基因与基因组百科全书（KEGG）、基因本体论（GO）、基因集富集分析（GSEA）和基因集变异分析（GSVA）以进行功能富集分析。最后，提取CIBERSORTx分析枢纽基因与各种免疫细胞之间的相关性。使用Starbase和JASPAR数据库构建枢纽RNA结合蛋白（RBPs）和长链非编码RNA-转录因子（TF）相互作用网络。正常组和COPD组肺组织样本之间共有1796个信使RNA、2207个长链非编码RNA和11个微小RNA表现出差异表达。基于这些DEGs分别构建了长链非编码RNA/环状RNA-微小RNA-信使RNA的ceRNA网络。此外，鉴定出10个枢纽基因。其中，核糖体蛋白S11（RPS11）、核糖体蛋白L32（RPL32）、核糖体蛋白L5（RPL5）和核糖体蛋白L27A（RPL27A）与肺组织增殖、分化和凋亡有关。生物学功能显示，肿瘤坏死因子-α（TNF-α）通过核因子-κB（NF-κB）和白细胞介素6/Janus激酶/信号转导子和转录激活子3（IL6/JAK/STAT3）信号通路参与COPD。我们的研究构建了长链非编码RNA/环状RNA-微小RNA-信使RNA的ceRNA网络，筛选出10个可能调控TNF-α/NF-κB、IL6/JAK/STAT3信号通路的枢纽基因，间接阐明了COPD的转录后调控机制，为挖掘COPD诊断和治疗的新靶点奠定了基础。
