L1CAM-ILK-YAP Mechanotransduction Drives Proliferative Activity of Epithelial Cells in Middle Ear Cholesteatoma
L1CAM-ILK-YAP Mechanotransduction Drives Proliferative Activity of Epithelial Cells in Middle Ear Cholesteatoma
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L1CAM-ILK-YAP 机械转导驱动中耳胆脂瘤上皮细胞的增殖活性
DOI：
10.1016/j.ajpath.2020.04.007
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Kojima Hiromi
中科院分区：
文献类型：
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作者：
Yamamoto-Fukuda Tomomi;Akiyama Naotaro;Kojima Hiromi
中耳乳突瘤是一种上皮细胞增生增强的慢性中耳炎。中耳负压被认为是中耳炎的重要病因。然而，中耳炎的形成机制仍不清楚。整合素连接蛋白激酶（ILK）是肌动蛋白细胞骨架动力学的重要调节因子，与细胞外基质相互作用，导致机械转导效应因子Yes相关蛋白（雅普）上调。L1细胞粘附分子（L1 CAM）最近被报道为与细胞增殖和迁移相关的机械转导效应物的激活剂。在这项研究中，我们证明了中耳培养细胞的拉伸试验，并进行免疫组化使用抗体对Ilk，雅普，和L1凸轮。还使用ILK、雅普、Ki-67和L1 CAM抗体的免疫组织化学分析了新的中耳负压动物模型和人中耳炎组织中的鼓膜。在负压负荷下增厚的鼓膜上皮和中耳瘤中，胞浆ILK表达增加，雅普核移位增加。在基质细胞中检测到L1 CAM的表达，其依赖于ILK信号传导事件而增强上皮细胞增殖。总之，我们证明了基质L1 CAM和上皮ILK-YAP信号传导在中耳炎形成的机械转导下的上皮生长中发挥重要作用的可能性。
Middle-ear cholesteatoma (cholesteatoma) is a chronic otitis media with an enhanced proliferation of epithelial cells. Negative pressure in the middle ear is thought to be important for the etiology of cholesteatoma. However, the mechanism of cholesteatoma formation remains unclear. Integrin-linked protein kinase (ILK), an important modulator of actin cytoskeletal dynamics, interacts with extracellular matrix and results in the up-regulation of mechanotransduction effector Yes-associated protein (YAP). The L1 cell adhesion molecule (L1CAM) has recently been reported as an activator of the mechanotransduction effectors related to cell proliferation and migration. In this study, we demonstrated a stretch assay for middle-ear cultured cells and performed immunohistochemistry using antibodies against Ilk, Yap, and L1cam. The tympanic membrane was also analyzed within a new middle-ear negative-pressure animal model and human cholesteatoma tissues, using immunohistochemistry with antibodies against ILK, YAP, Ki-67, and L1CAM. The expression of cytoplasmic ILK and nuclear shift of YAP increased in the thickened epithelium of the tympanic membrane under a negative-pressure load and the cholesteatoma. The expression of L1CAM was detected in the stromal cells, which enhanced epithelial cell proliferation depending on ILK signaling events. In conclusion, we demonstrated the possibility that the stromal L1CAM and epithelial ILK–YAP signaling played an important role in epithelial growth under mechanotransduction in cholesteatoma formation.