Zhang Jintao, Wang Zihan, Zhang Dong, Pan Yun, Liu Xiaofei, Qiao Xinrui, Cui Wenjing, Dong Liang
Department of Respiratory, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China.
Department of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong University, The First Affiliated Hospital of Shandong First Medical University, Shandong Institute of Respiratory Diseases, Jinan, People's Republic of China.
J Asthma Allergy. 2021 Oct 30;14:1307-1321. doi: 10.2147/JAA.S331090. eCollection 2021.
During asthma progression, the intricate molecular networks, including microRNA (miRNA) transcriptional regulation in airway epithelium, remain largely undefined. The abnormal expression of miRNAs in asthmatic airway epithelium is a recent and fast-growing area in developing diagnostic and therapeutic targets for asthma.
Analyses were conducted to compare airway epithelial miRNAs and gene expression between patients with asthma and healthy subjects from three datasets (two for miRNAs expression profiles and one for gene expression profile). The interactions network between differentially expressed (DE)-miRNAs and mRNAs was further identified for functional analysis. To verify the involvement and functions of all the identified miRNAs in asthma, we constructed two cellular models of asthma. The most promising causal miRNA candidate, miR-1246, was examined in an in vitro system to explore its targets and roles in asthma pathophysiology.
Through integrative analysis, we obtained six miRNAs with 31 validated target genes in airway epithelium associated with asthma. Next, we confirmed that these miRNAs were all associated with asthma progression by in vitro functional experiments. They may participate in eosinophilic inflammation (miR-92b-3p, miR-1246, miR-197-3p, and miR-124-5p) or remodeling (miR-197-3p, miR-193a-5p, miR-1246, and miR-92b-3p). Additionally, some other non-screened valuable miRNAs were also examined and identified (miR-21-5p and miR-19b-3p), and some detected in blood correlated with the disease status. Furthermore, we found that miR-1246 could directly target and influence epithelial-to-mesenchymal transition and fibrosis in airway epithelial cells.
We constructed a preliminary epithelial regulatory network in asthma based on six identified miRNAs and their valuable target genes. Candidate factors in the biological miRNA-mRNA network in airway epithelium may provide further information on the pathogenesis of asthma. Strikingly, among all screened miRNAs, miR-1246, which could interact with may have multifunctional effects in the course of asthma and be a promising agent for asthma treatment and molecular subtyping.
在哮喘进展过程中，包括气道上皮细胞中微小RNA（miRNA）转录调控在内的复杂分子网络在很大程度上仍不明确。哮喘气道上皮细胞中miRNA的异常表达是哮喘诊断和治疗靶点开发中一个新兴且快速发展的领域。
对来自三个数据集（两个用于miRNA表达谱，一个用于基因表达谱）的哮喘患者和健康受试者的气道上皮miRNA和基因表达进行分析比较。进一步确定差异表达（DE）-miRNA与mRNA之间的相互作用网络以进行功能分析。为了验证所有鉴定出的miRNA在哮喘中的参与情况和功能，我们构建了两种哮喘细胞模型。在体外系统中检测了最有前景的因果miRNA候选物miR-1246，以探索其在哮喘病理生理学中的靶点和作用。
通过综合分析，我们在气道上皮细胞中获得了6种miRNA及其31个经验证的与哮喘相关的靶基因。接下来，我们通过体外功能实验证实这些miRNA均与哮喘进展相关。它们可能参与嗜酸性粒细胞炎症（miR-92b-3p、miR-1246、miR-197-3p和miR-124-5p）或重塑（miR-197-3p、miR-193a-5p、miR-1246和miR-92b-3p）。此外，还检测并鉴定了一些其他未筛选的有价值的miRNA（miR-21-5p和miR-19b-3p），并且在血液中检测到的一些miRNA与疾病状态相关。此外，我们发现miR-1246可以直接靶向并影响气道上皮细胞的上皮-间质转化和纤维化。
我们基于6种鉴定出的miRNA及其有价值的靶基因构建了哮喘中初步的上皮调控网络。气道上皮细胞中生物miRNA-mRNA网络中的候选因子可能为哮喘的发病机制提供进一步信息。引人注目的是，在所有筛选出的miRNA中，能够与……相互作用的miR-1246在哮喘过程中可能具有多种功能作用，并且是哮喘治疗和分子分型的有前景的药物。
