Bauer Karin, Dowejko Albert, Bosserhoff A-K, Reichert T E, Bauer Richard Josef
Department of Oral and Maxillofacial Surgery, University of Regensburg, Regensburg, Germany.
Carcinogenesis. 2009 Oct;30(10):1781-8. doi: 10.1093/carcin/bgp175. Epub 2009 Jul 14.
Cadherins belong to a family of Ca(2+)-dependent homophilic cell-cell adhesion proteins that are important for correct cellular localization and tissue integrity. They play a major role in the development and homeostasis of epithelial architecture. Recently, it has become more and more evident that P-cadherin contributes to the oncogenesis of many tumors. To analyze the role of P-cadherin in oral squamous cell carcinoma (OSCC), we used a cell line that was deficient of the classical cadherins, P-cadherin, E-cadherin and N-cadherin. This cell line was transfected with full-length P-cadherin (PCI52_PC). After overexpression of P-cadherin, PCI52_PC gained an epithelial-like brickstone morphology in contrast to the mock-transfected cells with a spindle-shaped mesenchymal morphology. Immunohistochemical analysis revealed a strong nuclear Snail staining in mock-transfected cells compared with a significantly reduced nuclear staining and translocation to the cytoplasm in P-cadherin-overexpressing cells. Interestingly, the effects triggered by P-cadherin overexpression could be reversed by transfecting the cells with an antisense P-cadherin plasmid construct. Additional investigations showed a reexpression of E-cadherin in all P-cadherin-transfected cell clones in contrast to the mock controls. Analyzing the signaling mechanism behind it, we found glycogen-synthase-kinase-3beta (GSK-3beta) bound to Snail in all cell clones. Furthermore, P-cadherin-overexpressing cell lines showed activated GSK-3beta that phosphorylated Snail leading to its cytoplasmic translocation. In summary, our results reveal P-cadherin as one major component in reconfiguring mesenchymal cells with epithelial features by triggering GSK-3beta-mediated inactivation and cytoplasmatic translocation of Snail in OSCC.
钙黏蛋白属于一类依赖钙离子的同嗜性细胞间黏附蛋白家族，对细胞的正确定位和组织完整性至关重要。它们在上皮结构的发育和稳态中发挥着重要作用。最近，越来越明显的是，P-钙黏蛋白在许多肿瘤的发生中起作用。为了分析P-钙黏蛋白在口腔鳞状细胞癌（OSCC）中的作用，我们使用了一种缺乏经典钙黏蛋白、P-钙黏蛋白、E-钙黏蛋白和N-钙黏蛋白的细胞系。该细胞系用全长P-钙黏蛋白（PCI52_PC）进行转染。与转染空载体的具有纺锤形间充质形态的细胞相比，P-钙黏蛋白过表达后，PCI52_PC获得了上皮样的砖块状形态。免疫组织化学分析显示，与P-钙黏蛋白过表达细胞中核染色显著减少并转位至细胞质相比，转染空载体的细胞中Snail核染色较强。有趣的是，通过用反义P-钙黏蛋白质粒构建体转染细胞，可以逆转P-钙黏蛋白过表达引发的效应。进一步的研究表明，与空载体对照相比，所有P-钙黏蛋白转染的细胞克隆中E-钙黏蛋白重新表达。分析其背后的信号机制，我们发现在所有细胞克隆中糖原合酶激酶-3β（GSK-3β）与Snail结合。此外，P-钙黏蛋白过表达的细胞系显示GSK-3β活化，其磷酸化Snail导致其细胞质转位。总之，我们的结果表明，P-钙黏蛋白是通过触发OSCC中GSK-3β介导的Snail失活和细胞质转位来重新构建具有上皮特征的间充质细胞的一个主要成分。
