An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition.
An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition.
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DOI：
10.1091/mbc.e11-02-0103
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发表时间：
2011-05-15
影响因子：
3.3
通讯作者：
Goodall GJ
中科院分区：
文献类型：
--
作者：
Gregory PA;Bracken CP;Smith E;Bert AG;Wright JA;Roslan S;Morris M;Wyatt L;Farshid G;Lim YY;Lindeman GJ;Shannon MF;Drew PA;Khew-Goodall Y;Goodall GJ
上皮-间质转化是一种细胞可塑性的形式，对胚胎发育和肿瘤转移至关重要。这项研究表明，涉及自分泌TGF-β信号传导、ZEB转录因子和miR-200家族的信号传导网络调节上皮和间充质状态之间的相互转化。 上皮-间质转化（EMT）是一种细胞可塑性的形式，对胚胎发育和肿瘤转移至关重要。据推测，涉及miR-200家族和ZEB（锌指E-box结合同源盒）转录因子的双负反馈回路控制着上皮和间充质状态之间的平衡。在这里，我们使用上皮Madin达比犬肾细胞系模型证明，尽管ZEB/miR-200平衡的操纵能够在上皮和间充质状态之间反复切换细胞，但稳定的间充质表型的诱导和维持需要建立自分泌转化生长因子-β（TGF-β）信号传导以驱动持续的ZEB表达。此外，我们发现，延长的自分泌TGF-β信号转导诱导miR-200基因座的可逆DNA甲基化，并相应地改变miR-200水平。总的来说，这些发现证明了自分泌TGF-β/ZEB/miR-200信号网络的存在，其调节上皮和间充质状态之间的可塑性。我们发现，在浸润性导管癌中，ZEB和TGF-β之间存在强相关性，miR-200和TGF-β之间以及miR-200和ZEB之间存在负相关性，这与自分泌TGF-β/ZEB/miR-200信号网络在乳腺癌中活跃一致。
Epithelial-mesenchymal transition is a form of cellular plasticity that is critical for embryonic development and tumor metastasis. This study shows that a signaling network involving autocrine TGF-β signaling, ZEB transcription factors, and the miR-200 family regulates interconversion between epithelial and mesenchymal states. Epithelial-mesenchymal transition (EMT) is a form of cellular plasticity that is critical for embryonic development and tumor metastasis. A double-negative feedback loop involving the miR-200 family and ZEB (zinc finger E-box-binding homeobox) transcription factors has been postulated to control the balance between epithelial and mesenchymal states. Here we demonstrate using the epithelial Madin Darby canine kidney cell line model that, although manipulation of the ZEB/miR-200 balance is able to repeatedly switch cells between epithelial and mesenchymal states, the induction and maintenance of a stable mesenchymal phenotype requires the establishment of autocrine transforming growth factor-β (TGF-β) signaling to drive sustained ZEB expression. Furthermore, we show that prolonged autocrine TGF-β signaling induced reversible DNA methylation of the miR-200 loci with corresponding changes in miR-200 levels. Collectively, these findings demonstrate the existence of an autocrine TGF-β/ZEB/miR-200 signaling network that regulates plasticity between epithelial and mesenchymal states. We find a strong correlation between ZEBs and TGF-β and negative correlations between miR-200 and TGF-β and between miR-200 and ZEBs, in invasive ductal carcinomas, consistent with an autocrine TGF-β/ZEB/miR-200 signaling network being active in breast cancers.