Epidermal growth factor activates a hypoxia‐inducible factor 1α–microRNA‐21 axis to inhibit aquaporin 4 in chronic rhinosinusitis. Issue 1 (27th October 2022)

• Record Type: Journal Article
• Authors: Chen, Junjun; Liu, Dong; Yang, Jingpu; Jin, Chengxun; Zhao, Chang; Cheng, Jinzhang
• Is Part Of: Annals of the New York Academy of Sciences. Volume 1518:Issue 1(2022)
• Page Start: 299
• Page End: 314
• Publication Date: 2022-10-27
• Subjects: apoptosis -- AQP4 -- chronic rhinosinusitis -- EGF -- HIF‐1α -- human nasal epithelial cells -- microRNA‐21 -- migration -- proliferation; Medical sciences -- Periodicals; Medicine -- Periodicals; Science -- Periodicals; 610
• DOI: 10.1111/nyas.14914
• Languages: English
• ISSNs: 0077-8923

Abstract

Abstract: The pathogenesis of chronic rhinosinusitis (CRS) is largely unknown, but accumulating evidence supports the role of the airway epithelium in its pathophysiology. In our study here, we evaluated whether epidermal growth factor (EGF) regulates a hypoxia‐inducible factor 1α (HIF‐1α)–microRNA‐21 (miR‐21)–aquaporin 4 (AQP4) axis in nasal epithelial cells from CRS patients. We found that, compared with normal sinus mucosa, EGF, HIF‐1α, and miR‐21 were upregulated and AQP4 was downregulated in sinus mucosa from patients with CRS and in a CRS mouse model. It was established that EGF upregulated HIF‐1α and miR‐21 expression, that HIF‐1α regulated miR‐21 transcription, and that the AQP4 gene was a target of miR‐21. Knockdown of EGF and HIF‐1α mRNAs and of miR‐21, or overexpression of AQP4 mRNA, inhibited proliferation and promoted apoptosis of hypoxia‐exposed human nasal epithelial cells, effects that were associated with reduced levels of α‐SMA, fibronectin, and vimentin, as well as promoted caspase‐3 activity and E‐cadherin levels. In the mouse CRS model, EGF elevation increased in vivo production of inflammatory IL‐4 and IFN‐γ to promote CRS, which was reversed by AQP4 elevation. Collectively, EGF upregulates HIF‐1α and miR‐21 expression to inhibit AQP4 expression, thereby promoting the proliferation of nasal epithelial cells and the development of CRS. Abstract : The pathogenesis of chronic rhinosinusitis (CRS) is largely unknown, but accumulating evidence supports a role for the airway epithelium in its pathophysiology. In this study we show that epidermal growth factor upregulates hypoxia‐inducible factor 1α and microRNA‐21 expression to inhibit aquaporin 4 gene expression, thereby promoting proliferation of nasal epithelial cells and development of CRS.