Eger Andreas, Stockinger Andreas, Park John, Langkopf Elke, Mikula Mario, Gotzmann Josef, Mikulits Wolfgang, Beug Hartmut, Foisner Roland
Max F. Perutz Laboratories, University Departments at the Vienna Biocenter, Department of Medical Biochemistry, University of Vienna, Vienna, Austria.
Oncogene. 2004 Apr 8;23(15):2672-2680. doi: 10.1038/sj.onc.1207416.
Several signalling pathways contribute to the regulation of epithelial to mesenchymal transition (EMT), either during developmentally regulated processes or in cancer progression and metastasis. Induction of EMT in fully polarized mouse mammary epithelial cells (EpH4) by an inducible c-fos estrogen receptor (FosER) oncoprotein involves loss of E-cadherin expression, nuclear translocation of beta-catenin, and autocrine production of TGFbeta. Reporter assays demonstrate that both beta-catenin/LEF-TCF- and TGFbeta-Smad-dependent signalling activities are upregulated, probably coregulating mesenchymal-specific gene expression during EMT. Stable expression of E-cadherin in mesenchymal FosER cells decreased beta-catenin activity and reduced cell proliferation. However, these cells still exhibited a defect in epithelial polarization and expressed E-cadherin/beta-catenin complexes in the entire plasma membrane. On the other hand, inhibition of TGFbeta-Smad signalling in mesenchymal FosER cells induced flat, cobblestone-like clusters of cells, which relocalized beta-catenin to the plasma membrane but still lacked detectable E-cadherin. Interestingly, inhibition of TGFbeta signalling in the E-cadherin-expressing mesenchymal FosER cells caused their reversion to a polarized epithelial phenotype, in which E-cadherin, beta-catenin, and ZO-1 were localized at their correct lateral plasma membrane domains. These results demonstrate that loss of E-cadherin can contribute to increased LEF/TCF-beta-catenin signalling, which in turn cooperates with autocrine TGFbeta signalling to maintain an undifferentiated mesenchymal phenotype.
在发育调控过程或癌症进展及转移过程中，有几种信号通路参与上皮-间质转化（EMT）的调节。通过可诱导的c-fos雌激素受体（FosER）癌蛋白在完全极化的小鼠乳腺上皮细胞（EpH4）中诱导EMT，涉及E-钙黏蛋白表达的丧失、β-连环蛋白的核转位以及TGFβ的自分泌产生。报告基因分析表明，β-连环蛋白/LEF-TCF和TGFβ-Smad依赖的信号活性均上调，可能在EMT过程中共同调节间充质特异性基因表达。在间充质FosER细胞中稳定表达E-钙黏蛋白可降低β-连环蛋白活性并减少细胞增殖。然而，这些细胞在上皮极化方面仍存在缺陷，并且在整个质膜中表达E-钙黏蛋白/β-连环蛋白复合物。另一方面，在间充质FosER细胞中抑制TGFβ-Smad信号可诱导扁平的、鹅卵石样的细胞簇，使β-连环蛋白重新定位到质膜，但仍缺乏可检测到的E-钙黏蛋白。有趣的是，在表达E-钙黏蛋白的间充质FosER细胞中抑制TGFβ信号会导致它们恢复为极化的上皮表型，其中E-钙黏蛋白、β-连环蛋白和ZO-1定位于其正确的外侧质膜结构域。这些结果表明，E-钙黏蛋白的丧失可导致LEF/TCF-β-连环蛋白信号增加，进而与自分泌TGFβ信号协同作用以维持未分化的间充质表型。
