Epithelial plasticity, or epithelial-to-mesenchymal transition (EMT), is a well-recognized form of cellular plasticity, which endows tumor cells with invasive properties and alters their sensitivity to various agents, thus representing a major challenge to cancer therapy. It is increasingly accepted that carcinoma cells exist along a continuum of hybrid epithelial–mesenchymal (E-M) states and that cells exhibiting such partial EMT (P-EMT) states have greater metastatic competence than those characterized by either extreme (E or M). We described recently a P-EMT program operating in vivo by which carcinoma cells lose their epithelial state through post-translational programs. Here, we investigate the underlying mechanisms and report that prolonged calcium signaling induces a P-EMT characterized by the internalization of membrane-associated E-cadherin (ECAD) and other epithelial proteins as well as an increase in cellular migration and invasion. Signaling through Gαq-associated G-protein-coupled receptors (GPCRs) recapitulates these effects, which operate through the downstream activation of calmodulin-Camk2b signaling. These results implicate calcium signaling as a trigger for the acquisition of hybrid/partial epithelial–mesenchymal states in carcinoma cells.

中文翻译：

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钙信号传导诱导部分 EMT


上皮可塑性或上皮间质转化（EMT）是一种公认​​的细胞可塑性形式，它赋予肿瘤细胞侵袭性并改变其对各种药物的敏感性，从而对癌症治疗提出了重大挑战。人们越来越多地认识到，癌细胞沿着混合上皮-间质 (EM) 状态的连续体存在，并且表现出这种部分 EMT (P-EMT) 状态的细胞比具有极端状态（E 或 M）的细胞具有更强的转移能力。我们最近描述了一种在体内运行的 P-EMT 程序，癌细胞通过翻译后程序失去其上皮状态。在这里，我们研究了潜在的机制，并报告说，延长的钙信号传导会诱导 P-EMT，其特征是膜相关 E-钙粘蛋白 (ECAD) 和其他上皮蛋白的内化以及细胞迁移和侵袭的增加。通过 Gαq 相关 G 蛋白偶联受体 (GPCR) 的信号传导重现了这些效应，这些效应通过钙调蛋白-Camk2b 信号传导的下游激活发挥作用。这些结果表明钙信号传导是癌细胞获得混合/部分上皮-间质状态的触发因素。