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Partial Epithelial-Mesenchymal Transition Was Observed Under p63 Expression in Acquired Middle Ear Cholesteatoma and Congenital Cholesteatoma.

髙橋, 昌寛 東京慈恵会医科大学 DOI:info:doi/10.1097/MAO.0000000000002328

2020.10.15

概要

Epithelial mesenchymal transition (EMT) is a process by which the loss of epithelial cell– cell adhesions that promote a mesenchymal phenotype is observed, which enable migration and invasion ability (5). EMTs are thought to be associated with tumor progression and to occur during cancer metastasis (5). Cells undergoing EMT often display cadherin switching, in which they downregulate one cadherin and induce expression of another; for example, from E-cadherin (E-cad) to N- cadherin (N-cad) (6). This so-called ‘‘cadherin switch’’ changes the cell– cell adhesion molecules relative to those of its tissue of origin and has been proposed to be required for a cell undergoing EMT to separate from its neighbor cells (7). Tight junction components, claudin (CLD) and occludin (OCL), are another mode of cell– cell adhesion molecules and it has been shown that CLD1 promotes EMT in human bronchial epithelial cells (8) and the reduction of CLD4 induces EMT (9). However, in recent years many studies have failed to detect EMT, or have argued that EMT is not fully required for metastasis, leading to significant controversy in the field of oncology (10,11). An increasing number of studies have shown that during developmental and wound-heal- ing processes, cells undergo EMT and transition to a partial state; downregulating just a subset of epithelial characteristics and increasing only some mesenchymal traits, such as invasive motility (6). Under a partial EMT (p-EMT) status, EMT-like cells maintained the expres- sion of basal epithelial cell markers and did not express most of the transcription factors considered to be EMT master regulators (12).
　A master regulator of epidermal gene transcription is p63, and it plays an essential function in controlling epidermal development (13,14), and cell proliferation and stemness (15,16). We previously showed an increase in the expression of p63 in a cholesteatoma matrix (17). p63 is also known as one of the regulators of various cell matrix and cell–cell adhesion complexes in the epider- mis and controls cadherin family expression, inducing epithelial proliferation in human epithelial cells (18).
　For this study, we hypothesized that p-EMT under p63 expression may be one of the key factors in the prolifer- ative activities of epithelial cells in middle ear choles- teatoma. To address this hypothesis, we first analyzed the positive rates of p63 in the congenital cholesteatoma (CC) group, the acquired cholesteatoma (AC) group, and the normal skin group. We then addressed the expression level of tight junction markers (CLD1, CLD4, and OCL), the adherence junction marker E-cad, and the EMT marker N-cad in the CC, AC, and normal skin groups. Understanding these p-EMT and associated signaling events under physical factors can improve therapeutic outcomes in patients with middle ear cholesteatoma.

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