CircZNF652 promotes the goblet cell metaplasia by targeting the miR-452-5p/JAK2 signaling pathway in allergic airway epithelia

Background: Circular RNAs (circRNAs) play potentially important roles in various human diseases; however, their roles in the goblet cell metaplasia of asthma remain unknown. Objective: We sought to investigate the potential role and underlying mechanism of circZNF652 in the regulation of allergic airway epithelial remodeling. Methods: The differential expression profiles of circRNAs were analyzed by transcriptome microarray, and the effects and mechanisms underlying circZNF652-mediated goblet cell metaplasia were investigated by quantitative real-time PCR, RNA fluorescence in situ hybridization, Western blot, RNA pull-down, and RNA immunoprecipitation analyses. The roles of circZNF652 and miR-452-5p in allergic airway epithelial remodeling were explored in both the mouse model with allergic airway inflammation and children with asthma. Results: One hundred sixty circRNAs were differentially expressed in bronchoalveolar lavage fluid of children with asthma versus children with foreign body aspiration, and 52 and 108 of them were significantly upregulated and downregulated, respectively. Among them, circZNF652 was predominantly expressed and robustly upregulated in airway epithelia of both the children with asthma and the mouse model with allergic airway inflammation. circZNF652 promoted the goblet cell metaplasia by functioning as a sponge of miR-452-5p, which released the Janus kinase 2 (JAK2) expression and subsequently activated JAK2/signal transducer and activator of transcription 6 (STAT6) signaling in the allergic airway epithelia. In addition, epithelial splicing regulatory protein 1, a splicing factor, accelerated the biogenesis of circZNF652 by binding to its flanking intron to promote the goblet cell metaplasia in allergic airway epithelial remodeling. Conclusions: Upregulation of circZNF652 expression in allergic bronchial epithelia contributed to the goblet cell metaplasia by activating the miR-452-5p/JAK2/STAT6 signaling pathway; thus, blockage of circZNF652 or agonism of miR-452-5p provided an alternative approach for the therapeutic intervention of epithelial remodeling in allergic airway inflammation.

Automated summary

This study revealed the high expression of circZNF652 in bronchoalveolar lavage fluid of allergic asthma patients and its role in promoting pathological goblet cell metaplasia through activation of the miR-452-5p/JAK2/STAT6 signaling pathway. These findings provide new strategies for the therapeutic intervention of epithelial remodeling in allergic airway inflammation.