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

IF 3.4 3区 生物学 Q3 CELL BIOLOGY
Lingling Zeng, Li Xie, Jin Hu, Chao He, Aiguo Liu, Xiang Lu, Wen Zhou
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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.
骨蛋白驱动的部分上皮-间充质转化控制着中耳胆脂瘤的发展。
胆脂瘤是一种常见的中耳疾病。目前,手术切除是唯一的治疗方法,但患者面临复发的高风险。胆脂瘤的分子基础在很大程度上仍然未知。在这里,我们发现主要由分泌蛋白组成的骨化蛋白(OPN)在中耳胆脂瘤的发病过程中起着至关重要的作用。全局转录组分析显示,人胆脂瘤组织上皮特征丧失,免疫反应增强。中耳胆脂瘤的定量 RT-PCR 和免疫组化染色验证了上皮标志物的表达减少,以及间质标志物(包括 Vimentin 和 Fibronectin)的表达升高,但不包括 N-Cadherin、α-平滑肌肌动蛋白(α-SMA)或铁绒毛抑制蛋白 1(FSP1),这表明存在部分上皮-间质转化(EMT)状态。此外,人胆脂瘤组织中 OPN 的表达明显升高。用 OPN 处理可促进细胞增殖、存活和迁移,并导致永生人角质形成细胞的部分 EMT。重要的是,阻断 OPN 信号传导可明显改善 SD 大鼠的胆脂瘤样症状。我们的机理研究表明,AKT-锌指E盒结合同工酶2(ZEB2)轴介导了OPN的作用。总之,这些研究结果表明,以 OPN 信号传导为靶点是治疗中耳胆脂瘤的一种很有前景的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Cycle
Cell Cycle 生物-细胞生物学
CiteScore
7.70
自引率
2.30%
发文量
281
审稿时长
1 months
期刊介绍: Cell Cycle is a bi-weekly peer-reviewed journal of high priority research from all areas of cell biology. Cell Cycle covers all topics from yeast to man, from DNA to function, from development to aging, from stem cells to cell senescence, from metabolism to cell death, from cancer to neurobiology, from molecular biology to therapeutics. Our goal is fast publication of outstanding research.
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