Department of Cell Biology, University Medical Centre, Utrecht, The Netherlands.
PLoS One. 2013;8(1):e53238. doi: 10.1371/journal.pone.0053238. Epub 2013 Jan 3.
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-b 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-b in immortalized human mammary epithelial cells. SOX4 expression and activity are rapidly induced in the early stages of the TGF-b-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 b-catenin. Moreover, shRNA-mediated knockdown of SOX4 significantly delays TGF-b-induced mRNA and protein expression of mesenchymal markers. Taken together, these data suggest that TGF-b-mediated increased expression of SOX4 is required for the induction of a mesenchymal phenotype during EMT in human mammary epithelial cells.
上皮-间充质转化程序调控胚胎发育和组织稳态的各个方面，但该途径在癌症中的异常激活导致肿瘤进展和转移。TGF-β 通过诱导几个关键转录因子介导的转录变化，强力诱导上皮来源的癌症发生上皮-间充质转化。在这里，我们确定发育转录因子 SOX4 是 TGF-β 在永生化人乳腺上皮细胞中诱导的上皮-间充质转化的转录靶标。SOX4 的表达和活性在 TGF-β 诱导的上皮-间充质转化的早期阶段迅速诱导。我们证明 Sox4 的条件激活足以诱导 N-钙粘蛋白和其他间充质标志物（包括波形蛋白和纤维连接蛋白）的表达，但不能诱导完全的 EMT，因为 E-钙粘蛋白和 b-连环蛋白的表达没有变化。此外，shRNA 介导的 SOX4 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 SOX4 表达增加是在人乳腺上皮细胞 EMT 过程中诱导间充质表型所必需的。
