Sirtuin 1 attenuates nasal polypogenesis by suppressing epithelial-to-mesenchymal transition

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• 作者：Mingyu Lee ; BSc^a ; ^b ; ^&lowast ; ; Dae Woo Kim ; MD ; PhD^c ; ^&lowast ; ; Haejin Yoon ; PhD^a ; Daeho So ; BSc^a ; ^b ; Roza Khalmuratova ; MD ; PhD^a ; Chae-Seo Rhee ; MD ; PhD^d ; Jong-Wan Park ; MD ; PhD^a ; ^b ; ^e ; Hyun-Woo Shin ; MD ; PhD^a ; ^b ; ^d ; ^f ; ^{charlie@snu.ac.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Nasal polyposis ; epithelial-to-mesenchymal transition ; sirtuin 1 ; hypoxia-inducible factor 1 ; animal model
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：137
• 期：1
• 页码：87-98.e7
• 全文大小：4949 K

文摘

Nasal polyps (NPs) imply a refractory clinical course in patients with chronic rhinosinusitis (CRS). Previously, we showed that hypoxia-inducible factor (HIF) 1 could mediate nasal polypogenesis through epithelial-to-mesenchymal transition (EMT). Sirtuin 1 (SIRT1), a histone deacetylase, reportedly suppresses the transcriptional activity of HIF-1. Thus we hypothesized that SIRT1 attenuates nasal polyposis by inhibiting HIF-1–induced EMT.

Objective

15">We sought to determine the role of SIRT1 in patients with nasal polyposis.

Methods

The effects of SIRT1 on nasal polypogenesis were investigated in previously developed murine models. Immunohistochemistry, immunoblotting, and immunoprecipitation were done to evaluate SIRT1, EMT, and hypoxic markers in human nasal epithelial cells or sinonasal tissues from the mice and the patients with CRS with or without NPs.

Results

SIRT1 transgenic mice had significantly fewer mucosal lesions with epithelial disruption and fewer NPs than wild-type (WT) mice. In addition, resveratrol (a SIRT1 activator) treatment suppressed nasal polypogenesis in WT mice; however, sirtinol (a SIRT1 inhibitor) administration increased the polyp burden in SIRT1 transgenic mice. In sinonasal specimens from patients with CRS, SIRT1 was downregulated in the mucosa from patients with polyps compared with levels seen in patients without polyps. SIRT1 overexpression or activation reversed hypoxia-induced EMT in human nasal epithelial cells. The intranasal transfection of a small hairpin SIRT1 lentiviral vector induced more nasal polypoid lesions in SIRT1 transgenic mice. Finally, mucosal extracts from patients with CRS without NPs increased SIRT1 expression in nasal epithelial cells, whereas those from patients with CRS with NPs did not.

Conclusion

SIRT1 suppressed NP formation, possibly because of inhibition of HIF-1–induced EMT. Thus nasal epithelium SIRT1 might be a therapeutic target for NPs.