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

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.

KEYWORDS:

• Middle ear cholesteatoma
• Osteopontin
• partial epithelial-mesenchymal transition

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

L.Z. conceived the study, designed and performed the experiments, analyzed the data, and drafted the manuscript. L.X., J.H. and C.H. provided technical support. A.L. and X.L. analyzed the data. W.Z. edited the manuscript and obtained grant support.

Data availability statement

The data that support the conclusion of this study have been included in this manuscript or available from the corresponding authors upon reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15384101.2024.2345481

Additional information

Funding

This study was supported by the National Natural Science Foundation of China [81600806, to W.Z.].