Osteopontin-driven partial epithelial-mesenchymal transition governs the development of middle ear cholesteatoma

被引:1
|
作者
Zeng, Lingling [1 ]
Xie, Li [1 ]
Hu, Jin [1 ]
He, Chao [1 ]
Liu, Aiguo [1 ]
Lu, Xiang [1 ]
Zhou, Wen [2 ]
机构
[1] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Otolaryngol Head & Neck Surg, Wuhan 430030, Hubei, Peoples R China
[2] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Otolaryngol, Wuhan 430022, Hubei, Peoples R China
基金
中国国家自然科学基金;
关键词
Middle ear cholesteatoma; Osteopontin; partial epithelial-mesenchymal transition; CHRONIC OTITIS-MEDIA; EXPRESSION; COMPLICATIONS; HYPERPROLIFERATION; IDENTIFICATION; KERATINOCYTES; PATHOGENESIS; ACTIVATION; INHIBITOR; BLOCKADE;
D O I
10.1080/15384101.2024.2345481
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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, alpha-smooth muscle actin (alpha-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.
引用
收藏
页码:537 / 554
页数:18
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