EGF induces epithelial-mesenchymal transition through phospho-Smad2/3-Snail signaling pathway in breast cancer cells.
EGF induces epithelial-mesenchymal transition through phospho-Smad2/3-Snail signaling pathway in breast cancer cells.
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DOI：
10.18632/oncotarget.13116
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发表时间：
2016-12-20
期刊：
影响因子：
--
通讯作者：
Kim A
中科院分区：
文献类型：
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作者：
Kim J;Kong J;Chang H;Kim H;Kim A
上皮-间质转化（EMT）可促进肿瘤的侵袭、转移和对化疗或激素治疗的抵抗。EMT可由多种生长因子诱导，例如表皮生长因子（EGF）。大多数关于EMT的研究都集中在TGF-β-Smads信号转导上。EGF通过激活乳腺癌细胞MCF-7和MDA-MB-231中的Smad 2/3诱导EMT的机制尚不清楚。EGF处理后，Snail、vimentin和fibronectin的表达水平呈时间依赖性增加，而E-cadherin的表达水平下降。EGF诱导的磷酸化Smad 2/3和Snail的核共定位和癌细胞迁移被ERK 1/2抑制剂PD 98059和磷酸化Smad 2抑制剂SB 203580预处理抑制。Smad 2/3表达的敲低抑制了EGF诱导的Snail、波形蛋白、纤连蛋白的表达和癌细胞侵袭，表明在侵袭性较低的MCF-7细胞中获得了间充质和迁移表型。EGF可诱导MDA-MB-231细胞发生EMT，并通过ERK 1/2-phospho-Smad 2/3-Snail信号通路诱导细胞侵袭。我们已经发现，EGF刺激的Smad 2/3的激活上调了几个关键的EMT标志物，抑制E-钙粘蛋白的表达，促进EMT，增强MCF-7和MDA-MB-231乳腺癌细胞的迁移和侵袭。这种分子机制的鉴定可能为转移性乳腺癌治疗的发展提供新的分子靶点。
Epithelial-mesenchymal transition (EMT) can contribute to tumor invasion, metastasis, and resistance to chemotherapy or hormone therapy. EMT may be induced by a variety of growth factors, such as epidermal growth factor (EGF). Most studies regarding EMT have focused on TGF-β-Smads signaling. The mechanism of EGF-induced EMT via activation of the Smad2/3 in breast cancer cells, MCF-7 and MDA-MB-231, remains unclear. The expression levels of Snail, vimentin, and fibronectin were increased by EGF treatment in a time-dependent manner, while the expression level of E-cadherin was decreased. EGF-induced nuclear co-localization of phospho-Smad2/3 and Snail and cancer cell migration were inhibited by pretreatment with an ERK1/2 inhibitor, PD98059 and a phospho-Smad2 inhibitor, SB203580. Knockdown of Smad2/3 expression suppressed EGF-induced expressions of Snail, vimentin, fibronectin, and cancer cell invasion, suggesting an acquisition of the mesenchymal and migratory phenotype in less aggressive MCF-7 cells. Moreover, MDA-MB-231 cells were shown that EGF-induced EMT, and cell invasion through ERK1/2-phospho-Smad2/3-Snail signaling pathway. We have discovered that EGF-stimulated activation of Smad2/3 upregulated several key EMT markers, inhibited E-cadherin expression, promoted EMT, enhanced migration and invasion in MCF-7 and MDA-MB-231 breast cancer cells. Identification of this molecular mechanism may provide new molecular targets for the development of therapies for metastatic breast cancer.