Abstract
Background: Asthma is one of the most prevalent chronic respiratory diseases worldwide. Bronchial epithelial cells play a critical role in the pathogenesis of asthma. Circular RNAs (circRNAs) act as microRNA (miRNA) sponges to regulate downstream gene expression. However, the role of epithelial circRNAs in asthma remains to be investigated. This study aims to explore the potential circRNA-miRNA-messenger RNA (mRNA) regulatory network in asthma by integrated analysis of publicly available microarray datasets. Methods: Five mRNA microarray datasets derived from bronchial brushing samples from asthma patients and control subjects were downloaded from the Gene Expression Omnibus (GEO) database. The robust rank aggregation (RRA) method was used to identify robust differentially expressed genes (DEGs) in bronchial epithelial cells between asthma patients and controls. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to annotate the functions of the DEGs. Protein-protein interaction (PPI) analysis was performed to identify hub genes. Three miRNA databases (Targetscan, miRDB, and miRWalk) were used to predict the miRNAs which potentially target the hub genes. A miRNA microarray dataset derived from bronchial brushings was used to validate the miRNA-mRNA relationships. Finally, a circRNA-miRNA-mRNA network was constructed via the ENCORI database. Results: A total of 127 robust DEGs in bronchial epithelial cells between steroid-naïve asthma patients (n = 272) and healthy controls (n = 165) were identified from five mRNA microarray datasets. Enrichment analyses showed that DEGs were mainly enriched in several biological processes related to asthma, including humoral immune response, salivary secretion, and IL-17 signaling pathway. Nineteen hub genes were identified and were used to construct a potential epithelial circRNA-miRNA-mRNA network. The top 10 competing endogenous RNAs were hsa_circ_0001585, hsa_circ_0078031, hsa_circ_0000552, hsa-miR-30a-3p, hsa-miR-30d-3p, KIT, CD69, ADRA2A, BPIFA1, and GGH. Conclusion: Our study reveals a potential role for epithelial circRNA-miRNA-mRNA network in the pathogenesis of asthma.
Highlights
Asthma is a heterogeneous disease and is characterized by chronic airway inflammation
Enrichment analyses showed that differentially expressed genes (DEGs) were mainly enriched in several biological processes related to asthma, including humoral immune response, salivary secretion, and IL-17 signaling pathway
Our study reveals a potential role for epithelial circRNA-miRNA-messenger RNA (mRNA) network in the pathogenesis of asthma
Summary
Asthma is a heterogeneous disease and is characterized by chronic airway inflammation. CircRNAs might function as microRNA (miRNA) sponges and sequester miRNA away from mRNAs, indirectly regulate gene expression (Hsu and Coca-Prados, 1979; Jeck et al, 2013; Memczak et al, 2013; Chen, 2020) Such competing endogenous RNAs (ceRNA) mechanism has been considered a prominent function of circRNAs. Previous studies have revealed that circRNAs are involved in multiple biological processes including neuronal function (Piwecka et al, 2017; Kleaveland et al, 2018), pluripotency regulation (Yu et al, 2017), cell differentiation (Kristensen et al, 2018), and cancer progression (Wang et al, 2019a; Wong et al, 2020) via decoying miRNAs. MiRNAs constitute another major class of non-coding RNAs with approximately 22 nucleotides (Gebert and MacRae, 2019; Goodall and Wickramasinghe, 2021). This study aims to explore the potential circRNA-miRNA-messenger RNA (mRNA) regulatory network in asthma by integrated analysis of publicly available microarray datasets
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