SOX4 mediates TGF-β-induced expression of mesenchymal markers during mammary cell epithelial to mesenchymal transition.
SOX4 mediates TGF-β-induced expression of mesenchymal markers during mammary cell epithelial to mesenchymal transition.
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DOI：
10.1371/journal.pone.0053238
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Coffer PJ
中科院分区：
文献类型：
--
作者：
Vervoort SJ;Lourenço AR;van Boxtel R;Coffer PJ
上皮细胞向间充质细胞的转化程序调节胚胎发育和组织稳态的各个方面，但癌症中该途径的异常激活有助于肿瘤进展和转移。TGF-β通过诱导由几种关键转录因子介导的转录变化，在上皮来源的癌症中有效诱导上皮向间充质转变。在这里，我们确定发育转录因子SOX 4是永生化人乳腺上皮细胞中TGF-β的转录靶点。S 0X 4表达和活性在TGF-β诱导的上皮向间充质转变的早期阶段被快速诱导。我们证明，Sox 4的条件性激活足以诱导N-钙粘蛋白和其他间充质标志物（包括波形蛋白和纤连蛋白）的表达，但不能诱导完全EMT，因为在E-钙粘蛋白和β-连环蛋白的表达中没有观察到变化。此外，shRNA介导的SOX 4敲低显著延迟TGF-β诱导的间充质标志物的mRNA和蛋白表达。总之，这些数据表明，TGF-β介导的SOX 4表达增加是在人乳腺上皮细胞中EMT期间诱导间充质表型所必需的。
The epithelial to mensenchymal transition program regulates various aspects of embryonic development and tissue homeostasis, but aberrant activation of this pathway in cancer contributes to tumor progression and metastasis. TGF-β potently induces an epithelial to mensenchymal transition in cancers of epithelial origin by inducing transcriptional changes mediated by several key transcription factors. Here, we identify the developmental transcription factor SOX4 as a transcriptional target of TGF-β in immortalized human mammary epithelial cells. SOX4 expression and activity are rapidly induced in the early stages of the TGF-β-induced epithelial to mensenchymal transition. We demonstrate that conditional activation of Sox4 is sufficient to induce the expression of N-cadherin and additional mesenchymal markers including vimentin and fibronectin, but fails to induce complete EMT as no changes are observed in the expression of E-cadherin and β-catenin. Moreover, shRNA-mediated knockdown of SOX4 significantly delays TGF-β-induced mRNA and protein expression of mesenchymal markers. Taken together, these data suggest that TGF-β-mediated increased expression of SOX4 is required for the induction of a mesenchymal phenotype during EMT in human mammary epithelial cells.
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