The T box transcription factor TBX2 promotes epithelial-mesenchymal transition and invasion of normal and malignant breast epithelial cells.
The T box transcription factor TBX2 promotes epithelial-mesenchymal transition and invasion of normal and malignant breast epithelial cells.
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DOI：
10.1371/journal.pone.0041355
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Briegel KJ
中科院分区：
文献类型：
--
作者：
Wang B;Lindley LE;Fernandez-Vega V;Rieger ME;Sims AH;Briegel KJ
T盒转录因子TBX2是器官发生的主要调节因子，在侵袭性人类上皮性肿瘤中异常扩增。虽然已经证明过表达TBX2可以绕过衰老，而衰老是一种抗癌的失败机制，但它在肿瘤侵袭中的潜在作用仍不清楚。在这里，我们证明了TBX2是上皮-间充质转化(EMT)的强大细胞自主诱导者，EMT是一种潜在的形态发生程序，是肿瘤从非侵袭性状态向侵袭性状态发展的关键。TBX2在正常的HC11和MCF10A乳腺上皮细胞中的异位表达足以诱导具有EMT特征的形态、分子和行为改变。这些变化包括上皮黏附和极性基因(E-钙粘蛋白、？连环蛋白、ZO1)的表达丧失，间质标志物(N-钙粘蛋白、Vimentin)的异常增加，以及细胞运动性和侵袭性的增加。相反，在恶性人类乳腺癌细胞系MDA-MB-435和MDA-MB-157中，内源性TBX2过表达的取消导致上皮特征的恢复，间质标志物的对等丢失。重要的是，抑制TBX2抑制了异种移植小鼠模型中肿瘤细胞的侵袭和形成肺转移的能力。对1000多个原发人类乳腺肿瘤的基因表达的荟萃分析进一步表明，高表达的TBX2与患者无转移生存期的降低显著相关，并与EMT基因特征丰富的肿瘤亚型相关，这与TBX2在致癌EMT中的作用一致。芯片分析和基于细胞的报告分析进一步表明，TBX2直接抑制肿瘤抑制基因E-钙粘素的转录，E-钙粘附素的缺失对恶性肿瘤的进展至关重要。总而言之，我们的结果揭示了癌症中TBX2的解除调控与获得EMT和上皮性肿瘤细胞的侵袭特征之间的意想不到的联系。
The T box transcription factor TBX2, a master regulator of organogenesis, is aberrantly amplified in aggressive human epithelial cancers. While it has been shown that overexpression of TBX2 can bypass senescence, a failsafe mechanism against cancer, its potential role in tumor invasion has remained obscure. Here we demonstrate that TBX2 is a strong cell-autonomous inducer of the epithelial-mesenchymal transition (EMT), a latent morphogenetic program that is key to tumor progression from noninvasive to invasive malignant states. Ectopic expression of TBX2 in normal HC11 and MCF10A mammary epithelial cells was sufficient to induce morphological, molecular, and behavioral changes characteristic of EMT. These changes included loss of epithelial adhesion and polarity gene (E-cadherin, ß-catenin, ZO1) expression, and abnormal gain of mesenchymal markers (N-cadherin, Vimentin), as well as increased cell motility and invasion. Conversely, abrogation of endogenous TBX2 overexpression in the malignant human breast carcinoma cell lines MDA-MB-435 and MDA-MB-157 led to a restitution of epithelial characteristics with reciprocal loss of mesenchymal markers. Importantly, TBX2 inhibition abolished tumor cell invasion and the capacity to form lung metastases in a Xenograft mouse model. Meta-analysis of gene expression in over one thousand primary human breast tumors further showed that high TBX2 expression was significantly associated with reduced metastasis-free survival in patients, and with tumor subtypes enriched in EMT gene signatures, consistent with a role of TBX2 in oncogenic EMT. ChIP analysis and cell-based reporter assays further revealed that TBX2 directly represses transcription of E-cadherin, a tumor suppressor gene, whose loss is crucial for malignant tumor progression. Collectively, our results uncover an unanticipated link between TBX2 deregulation in cancer and the acquisition of EMT and invasive features of epithelial tumor cells.
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