Osteopontin-driven partial epithelial-mesenchymal transition governs the development of middle ear cholesteatoma.
Cell Cycle
; 23(5): 537-554, 2024 Mar.
Article
em En
| MEDLINE
| ID: mdl-38662954
ABSTRACT
Cholesteatoma is a common disease of the middle ear. Currently, surgical removal is the only treatment option and patients face a high risk of relapse. The molecular basis of cholesteatoma remains largely unknown. Here, we show that Osteopontin (OPN), a predominantly secreted protein, plays a crucial role in the development of middle ear cholesteatoma. Global transcriptome analysis revealed the loss of epithelial features and an enhanced immune response in human cholesteatoma tissues. Quantitative RT-PCR and immunohistochemical staining of middle ear cholesteatoma validated the reduced expression of epithelial markers, as well as the elevated expression of mesenchymal markers including Vimentin and Fibronectin, but not N-Cadherin, α-smooth muscle actin (α-SMA) or ferroptosis suppressor protein 1 (FSP1), indicating a partial epithelial-mesenchymal transition (EMT) state. Besides, the expression of OPN was significantly elevated in human cholesteatoma tissues. Treatment with OPN promoted cell proliferation, survival and migration and led to a partial EMT in immortalized human keratinocyte cells. Importantly, blockade of OPN signaling could remarkably improve the cholesteatoma-like symptoms in SD rats. Our mechanistic study demonstrated that the AKT-zinc finger E-box binding homeobox 2 (ZEB2) axis mediated the effects of OPN. Overall, these findings suggest that targeting the OPN signaling represents a promising strategy for the treatment of middle ear cholesteatoma.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Ratos Sprague-Dawley
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Colesteatoma da Orelha Média
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Proliferação de Células
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Osteopontina
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Transição Epitelial-Mesenquimal
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Cell Cycle
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China