Forkhead transcription factor foxq1 promotes epithelial-mesenchymal transition and breast cancer metastasis.
Forkhead transcription factor foxq1 promotes epithelial-mesenchymal transition and breast cancer metastasis.
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DOI：
10.1158/0008-5472.can-10-2825
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发表时间：
2011-02-15
期刊：
影响因子：
11.2
通讯作者：
Wu G
中科院分区：
文献类型：
--
作者：
Zhang H;Meng F;Liu G;Zhang B;Zhu J;Wu F;Ethier SP;Miller F;Wu G
上皮-间质转化（Epithelial-mesenchymal transition， EMT）促进癌症侵袭和转移，但协调这些过程的综合机制尚不完全清楚。在这项研究中，我们在人类和小鼠的转移细胞系中使用跨物种表达谱策略来鉴定22个上调和12个下调的基因，这些基因是转移过程中必不可少的遗传程序的一部分。特别是，我们发现了叉头盒Q1 （Foxq1）转录因子在转移中的新功能，这是以前所不知道的。Foxq1的异位表达增加了细胞在体外的迁移和侵袭，增强了体内乳腺上皮细胞的肺转移能力，并引发了显著的EMT。相比之下，Foxq1敲低在体内和体外都会对这些表型产生相反的影响。Foxq1的异位表达和敲低均未显著影响体外细胞增殖或集落形成。值得注意的是，Foxq1通过结合其启动子区域的E-box来抑制核心EMT调节因子E-cadherin的表达。进一步的机制研究发现Foxq1的表达受TGF-β1的调控，Foxq1的敲低在形态学和分子水平上阻断TGF-β1诱导的EMT。我们的研究结果强调了跨物种表达谱作为一种鉴定转移相关基因的策略的可行性，他们揭示了EMT诱导可能是Foxq1在乳腺癌中新定义的促进转移功能的机制。
Epithelial-mesenchymal transition (EMT) promotes cancer invasion and metastasis, but the integrative mechanisms that coordinate these processes are incompletely understood. In this study, we used a cross-species expression profiling strategy in metastatic cell lines of human and mouse origin to identify 22 up-regulated and 12 down-regulated genes that are part of an essential genetic program in metastasis. In particular, we identified a novel function in metastasis that was not previously known for the transcription factor Forkhead Box Q1 (Foxq1). Ectopic expression of Foxq1 increased cell migration and invasion in vitro, enhanced the lung metastatic capabilities of mammary epithelial cells in vivo, and triggered a marked EMT. In contrast, Foxq1 knockdown elicited converse effects on these phenotypes in vitro and in vivo. Neither ectopic expression nor knockdown of Foxq1 significantly affected cell proliferation or colony formation in vitro. Notably, Foxq1 repressed expression of the core EMT regulator E-cadherin by binding to the E-box in its promoter region. Further mechanistic investigation revealed that Foxq1 expression is regulated by TGF-β1, and that Foxq1 knockdown blocked TGF-β1-induced EMT at both morphological and molecular levels. Our findings highlight the feasibility of cross-species expression profiling as a strategy to identify metastasis-related genes, and they reveal that EMT induction is a likely mechanism underlying a novel metastasis-promoting function of Foxq1 defined here in breast cancer.