PP2A Promotes Epithelial-Mesenchymal Transition in Chronic Rhinosinusitis with Nasal Polyps via Wnt/β-Catenin Pathway: A Novel Insight

Wei Chen,* Bowen Zheng,* Longlan Shu, Yijun Liu, Tao Lu, Yang Shen, Yucheng Yang Department of Otolaryngology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yucheng Yang, Department of Otolaryngology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China, Email [email protected] Yang Shen, Department of Otolaryngology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China, Email [email protected]: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a prevalent upper respiratory disease with eosinophilic infiltration. Epithelial-to-mesenchymal transition (EMT) has been considered an important pathological mechanism of CRSwNP. The Wnt signaling pathway is a well-established promoter of EMT, while Protein Phosphatase 2A (PP2A) exerts dual regulatory effects on Wnt pathway. However, the contribution of PP2A to CRSwNP has not been reported. This research aimed to explore the possible mechanisms by which PP2A modulates EMT in CRSwNP.Patients and Methods: About 56 patients with CRSwNP and 20 control subjects were enrolled in this study. We collected nasal polyps (NPs) and inferior turbinate tissues; the expression of PP2A, EMT markers, and Wnt signaling-related mediators in tissues were analyzed by Western blotting, immunohistochemistry, and quantitative RT-PCR. Primary cells isolated from NPs were cultured with PP2A inhibitor LB-100. The rhWNT3A-induced EMT cell model using BEAS-2B cell line was established in vitro and treated with either LB-100 or the PP2A agonist DT-061. Murine NP model was developed in vivo and treated with LB-100. The expression changes of EMT markers and Wnt signaling mediators were detected using Western blotting, immunofluorescence staining, and hematoxylin-eosin staining to estimate the effect of PP2A in the pathogenesis of CRSwNP.Results: Compared to controls, NPs exhibited increased PP2A expression and activity, activation of Wnt signaling, and evidence of EMT. These changes were more pronounced in eosinophilic NPs. PP2A inhibition alleviated, whereas PP2A activation promoted, EMT in epithelial cells by regulating Wnt pathway. PP2A inhibition could also suppress the formation of NPs and alleviate eosinophilic inflammation in the murine NP models.Conclusion: PP2A promotes EMT through the activation of Wnt/β-catenin signaling pathway, leading to epithelial barrier dysfunction in NPs. PP2A exerts a positive regulatory effect on the modulation of Wnt signaling in CRSwNP. Targeting PP2A might represent a viable therapeutic option for treating CRSwNP. Keywords: chronic rhinosinusitis, protein phosphatase 2A, epithelial-mesenchymal transition, nasal polyps, wnt