Negative feedback loop between p66Shc and ZEB1 regulates fibrotic EMT response in lung cancer cells.
Negative feedback loop between p66Shc and ZEB1 regulates fibrotic EMT response in lung cancer cells.
复制标题
p66(Shc) 和 ZEB1 之间的负反馈环调节肺癌细胞中纤维化 EMT 反应
DOI：
10.1038/cddis.2015.74
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发表时间：
2015-04-02
影响因子：
9
通讯作者：
Ma Z
中科院分区：
文献类型：
--
作者：
Li X;Gao D;Wang H;Li X;Yang J;Yan X;Liu Z;Ma Z
上皮细胞向间质细胞转化（EMT）过程在上皮癌的进展和纤维化疾病中起着关键作用。我们以前的工作已经证明，p66 Shc，一个局灶性粘附相关的衔接蛋白，在肺癌中经常下调，它的消耗通过抗失巢凋亡促进转移行为。然而，p66 Shc和EMT反应的损失的潜在机制尚未完全理解。在这里，我们发现p66 Shc缺陷增强了ZEB 1（已知的间充质转录因子）的表达，从而增加了波形蛋白，并减少了上皮细胞标志物E-钙粘蛋白和β-连环蛋白。p66 Shc缺失也增加了细胞的侵袭和迁移。此外，ChIP和荧光素酶分析表明，这些影响是直接介导的ZEB 1阻遏p66 Shc启动子。因此，我们的研究结果定义了一个关键的作用，p66 Shc在抑制纤维化EMT反应与负反馈环之间的p66 Shc和ZEB 1在肺上皮癌细胞。
The epithelial-to-mesenchymal transition (EMT) program is crucial for the epithelial cancer progression and fibrotic diseases. Our previous work has demonstrated that p66 Shc, a focal adhesion-associated adaptor protein, is frequently downregulated in lung cancers and its depletion promotes metastasis behavior through anoikis resistance. However, mechanism underlying loss of p66 Shc and EMT response is not fully understood. Here, we showed that p66 Shc deficiency enhanced the expression of ZEB1, the known mesenchymal transcription factor and consequently increased Vimentin, and decreased epithelial markers of E-cadherin and β-catenin. p66 Shc depletion also increased cell invasion and migration. In addition, ChIP and luciferase assays showed that these effects were directly mediated by ZEB1 repression of p66 Shc promoter. Thus, our findings define a critical role of p66 Shc in the suppression of fibrotic EMT response with a negative feedback loop between p66 Shc and ZEB1 in lung epithelial cancer cells.