한빛사 논문
Abstract
Hyun-Woo Shin1, Kumsun Cho1, Dae Woo Kim2, Doo Hee Han3, Roza Khalmuratova2, Sang-Wook Kim2, Sea-Yuong Jeon2, Yang-Gi Min3, Chul Hee Lee3, Chae-Seo Rhee3 and Jong-Wan Park1,*
1Department of Pharmacology and Biomedical Science, Ischemic/hypoxic disease institute, Seoul National University College of Medicine, Seoul, Korea
2Department of Otorhinolaryngology, Gyeongsang Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea
3Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul, Korea
*Correspondence: Jong-Wan Park, M.D., Ph.D. Department of Pharmacology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Korea.
Abstract
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. The authors hypothesized that hypoxia drives nasal polyposis via epithelial-to-mesenchymal transition (EMT).
Methods: Immunoblotting, immunofluorescence, and flow cytometry and real-time PCR were done to evaluate EMT and hypoxic markers in human nasal epithelial cells (hNECs) and in sinonasal tissues from CRS patients with or without polyps. In addition, the effects of HIF-1α inhibitors on nasal polypogenesis were investigated in a murine model.
Measurements and Main Results: E-cadherin and α-smooth muscle actin (α-SMA) were downregulated and upregulated, 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 (α-SMA, vimentin and twist) increased but epithelial markers (E-cadherin and β-catenin) decreased. Mechanistically, E-cadherin level was recovered in hypoxia by silencing HIF-1α and decreased in normoxia by expressing HIF-1α. Furthermore, hypoxia was found to downregulate PP2Ac phosphatase and upregulate pSmad3, which led to α-SMA induction. In CRS sinonasal specimens, HIF-1α expression was found to correlate with E-cadherin loss and α-SMA expression. Finally, HIF-1α inhibitors suppressed nasal polypogenesis in a murine model.
Conclusion: hNECs undergo EMT during hypoxia and this process is critically mediated by HIF-1α and pSmad3. This study shows that hypoxia-induced EMT is likely to contribute to nasal polyposis in CRS, and suggests that HIF-1α be viewed as a therapeutic target for nasal polyposis.
nasal polyposis, epithelial-to-mesenchymal transition, hypoxia, hypoxia-inducible factor 1, Smad3
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