Effects of Wnt signaling on epithelial to mesenchymal transition in chronic rhinosinusitis with nasal polyp

• Published in: Thorax Vol. 75; no. 11; pp. 982 - 993
• Main Authors: Bae, Jun-Sang, Ryu, Gwanghui, Kim, Ji Hye, Kim, Eun Hee, Rhee, Yun Hee, Chung, Young-Jun, Kim, Dae Woo, Lim, Suha, Chung, Phil-Sang, Shin, Hyun-Woo, Mo, Ji-Hun
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and British Thoracic Society 01.11.2020; BMJ Publishing Group LTD
• Subjects: Actins - metabolism; Adenomatous Polyposis Coli Protein; airway epithelium; Animals; Asthma; beta Catenin - metabolism; Biomarkers - metabolism; Cadherins - metabolism; Cell adhesion & migration; Chronic obstructive pulmonary disease; Cyclin D1 - metabolism; cytokine biology; Cytokines; Disease Models, Animal; Epithelial-Mesenchymal Transition - physiology; Gene expression; Genetic disorders; histology/cytology; Humans; Indocyanine Green - pharmacology; Inflammation; innate immunity; Mice; Nasal Polyps - drug therapy; Nasal Polyps - physiopathology; Neutrophils; Polyps; Respiratory research; Rhinitis; Rhinitis - physiopathology; Sinusitis; Sinusitis - physiopathology; Twist-Related Protein 1 - metabolism; Up-Regulation; Wnt Signaling Pathway - physiology; South Korea; California; United States > US; Japan; innate immunity; cytokine biology; airway epithelium; histology/cytology
• ISSN: 0040-6376; 1468-3296; 1468-3296
• DOI: 10.1136/thoraxjnl-2019-213916

BackgroundEpithelial to mesenchymal transition (EMT) is associated with the pathophysiology of chronic rhinosinusitis with nasal polyp (CRSwNP). Wnt signaling is causative for EMT, whereas the mechanism in CRSwNP is not fully understood.ObjectiveWe sought to evaluate the role of Wnt signaling in EMT of CRSwNP using a murine nasal polyp (NP) model and human tissues.MethodsInflammatory markers and EMT-related molecules were evaluated in NP models using adenomatosis polyposis coli (Apc)Min/+ mice with activated Wnt signaling and NP models treated with Wnt signaling inhibitor, indocyanine green-001 (ICG-001). EMT markers and Wnt signaling-associated mediators were analysed using human sinonasal tissues from control subjects and CRSwNP patients.ResultsApcMin/+ mice-induced NPs exhibited more frequent polypoid lesions and upregulation of Wnt-related molecules, including nuclear β-catenin, WNT3A and cyclin D1. Markers of EMT were significantly overexpressed in the ApcMin/+ NP mice (p<0.001 for E-cadherin and α-smooth muscle actin), and interleukin (IL)-17A+ cells and neutrophilic infiltration were increased in ApcMin/+ NP mice (p<0.001). Inhibition of Wnt signaling via ICG-001 resulted in significantly decreased nasal polypoid lesions (p<0.001), EMT-related markers (p=0.019 for E-cadherin and p=0.002 for vimentin) and the mRNA levels of IL-4 (p<0.001) and IL-17A (p=0.004) compared with the positive control group. Finally, nuclear β-catenin (p=0.042) was significantly increased compared with the control, and the expression levels of Wnt ligands and receptors were upregulated in human NP tissues (p=0.045 for WNT3A and p=0.042 for FZD2), suggesting increased Wnt signaling and EMT in CRSwNP.ConclusionWnt signaling may contribute to the pathogenesis of NPs through EMT. Therefore, inhibition of Wnt signaling may be a potential therapeutic strategy for patients with CRSwNP.