The morphogenic function of E-cadherin-mediated adherens junctions in epithelial ovarian carcinoma formation and progression
The morphogenic function of E-cadherin-mediated adherens junctions in epithelial ovarian carcinoma formation and progression
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DOI：
10.1111/j.1432-0436.2007.00193.x
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发表时间：
2008-02-01
期刊：
影响因子：
2.9
通讯作者：
Roskelley, Calvin D.
中科院分区：
文献类型：
--
作者：
Wu, Colleen;Cipollone, Jane;Roskelley, Calvin D.
E-钙粘附素在上皮性卵巢癌中的表达异常调节。它在粘附性较差的卵巢表面上皮(OSE)靶细胞中不表达，但在粘附性癌前病变和高粘附性、分化良好的肿瘤中表达，在这些肿瘤中它是膜相关的，推测是在粘连的连接处。在晚期侵袭性肿瘤中，E-钙粘附素的表达随后被抑制，或者其功能被破坏。在这里，我们观察到卵巢癌细胞中E-钙粘蛋白表达的增加与E-钙粘蛋白启动子活性的增加、粘连连接形成的增加、β-连环蛋白信号依赖的Lef-1活性的降低以及基底膜凝胶培养中粘连球体的产生有关。在永生化的OSE细胞中强制表达野生型E-钙粘蛋白启动了粘连连接的形成，降低了Lef-1的活性，减少了OSE细胞在单层培养中的间质迁移，并诱导了基底膜凝胶中粘连球体的形成。相反，在卵巢癌细胞中强制表达显性-负性E-钙粘附素突变体破坏了粘连连接，增加了间充质细胞的迁移，并在不改变Lef-1信号的情况下阻止了球形形态的形成。因此，除了抑制晚期肿瘤的进展，E-钙粘附素介导的黏附连接也可能有助于最初出现凝聚的形态发生表型，这是分化的上皮性卵巢癌的标志。
E-cadherin expression is unusually regulated in epithelial ovarian carcinoma. It is not expressed in poorly cohesive ovarian surface epithelial (OSE) target cells, but is expressed in cohesive pre-malignant lesions and in highly cohesive, well-differentiated tumors where it is membrane associated, presumably in adherens junctions. E-cadherin expression is subsequently suppressed, or its function is disrupted, in late-stage invasive tumors. Here, we observed that increased E-cadherin expression in ovarian carcinoma cells was associated with increased E-cadherin promoter activity, increased adherens junction formation, decreased beta-catenin signaling-dependent LEF-1 activity, and the generation of cohesive spheroids in basement membrane gel culture. Forced expression of wild-type E-cadherin in immortalized OSE cells initiated adherens junction formation, decreased LEF-1 activity, decreased the mesenchymal migration that is a characteristic of OSE cells that have been maintained in monolayer culture, and induced the formation of cohesive spheroids in basement membrane gels. Conversely, forced expression of a dominant-negative E-cadherin mutant in ovarian carcinoma cells disrupted adherens junctions, increased mesenchymal cell migration, and prevented spheroidal morphogenesis without altering LEF-1 signaling. Therefore, in addition to suppressing late-stage tumor progression, E-cadherin-mediated adherens junctions may also contribute to the initial emergence of a cohesive morphogenic phenotype that is a hallmark of differentiated epithelial ovarian carcinoma.