Hypoxia-inducible Factor 1 Mediates Nasal Polypogenesis by Inducing Epithelial-to-Mesenchymal Transition

초록

Rationale Nasal polyposis implies a refractory clinical course in case of chronic rhinosinusitis (CRS). Although hypoxia is believed to be associated with nasal polyposis, little is known about the mechanism underlying polypogenesis. Objectives: To determine if hypoxia drives nasal polyposis by epithelial-to-mesenchymal transition (EMT). Methods: Immunoblotting, immunofluorescence, flow cytometry, and real-time polymerase chain reaction were performed to evaluate EMT and hypoxic markers in human nasal epithelial cells (hNECs) and in sinonasal tissues from patients with CRS with or without polyps. In addition, the effects of hypoxia-inducible factor (HIF)-1 alpha inhibitors on nasal polypogenesis were investigated in a murine model. Measurements and Main Results: E-cadherin and a-smooth muscle actin (alpha-SMA) were down-regulated and up-regulated, respectively, in patients with polyps as compared with patients without polyps. Under hypoxia, hNECs transformed to a mesenchymal shape, and demonstrated representative changes in EMT markers; that is, mesenchymal markers (alpha-SMA, vimentin, and twist) increased but epithelial markers (E-cadherin and beta-catenin) decreased. Mechanistically, E-cadherin level was recovered in hypoxia by silencing HIF-1 alpha and decreased in normoxia by expressing HIFI a. Furthermore, hypoxia was found to down-regulate PP2Ac phosphatase and up-regulate pSmad3, which led to a-SMA induction. In CRS sinonasal specimens, HIF-1 alpha expression was found to correlate with E-cadherin loss and alpha-SMA expression. Finally, HIF-1 alpha inhibitors suppressed nasal polypogenesis in a murine model. Conclusions: hNECs undergo EMT during hypoxia and this process is critically mediated by HIF-1 alpha and pSmad3. This study shows that hypoxia-induced EMT is likely to contribute to nasal polyposis in CRS, and suggests that HIF-1 alpha be viewed as a therapeutic target for nasal polyposis.

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