Homeoprotein Six1 increases TGF-beta type I receptor and converts TGF-beta signaling from suppressive to supportive for tumor growth.
Homeoprotein Six1 increases TGF-beta type I receptor and converts TGF-beta signaling from suppressive to supportive for tumor growth.
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DOI：
10.1158/0008-5472.can-10-1354
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发表时间：
2010-12-15
期刊：
影响因子：
11.2
通讯作者：
Ford HL
中科院分区：
文献类型：
--
作者：
Micalizzi DS;Wang CA;Farabaugh SM;Schiemann WP;Ford HL
Six1同源结构域蛋白是一种发育转录因子，与肿瘤的发生和进展有关。我们近期的研究表明，在人乳腺癌细胞系中Six1的过度表达足以诱导上皮 - 间质转化（EMT）和转移。重要的是，Six1诱导的EMT和转移依赖于转化生长因子 - β（TGF - β）信号通路。TGF - β通路在癌症中具有双重作用，在早期病变中作为肿瘤抑制因子，但在更晚期的肿瘤中会促进转移扩散。我们之前的研究表明，Six1可能是TGF - β信号从肿瘤抑制转变为肿瘤促进的关键介质。然而，直到现在，Six1影响TGF - β通路的机制仍不清楚。在这项研究中，我们确定TGF - β I型受体（TβRI）是Six1的一个靶标，也是Six1诱导的TGF - β信号和EMT的关键效应因子。我们证明Six1诱导的TβRI上调对于激活TGF - β信号和诱导EMT特性既是必要的也是充分的。有趣的是，TβRI表达增加并不足以诱导实验性转移，这提供了体内证据表明Six1过度表达是将TGF - β信号转换为促转移表型所必需的，并证明诱导EMT不足以诱导实验性转移。总之，这些结果揭示了一种激活TGF - β信号的新机制，确定TβRI是Six1的一个新靶标，并表明Six1是乳腺癌中TGF - β功能的一个决定因素。
The Six1 homeodomain protein is a developmental transcription factor that has been implicated in tumor onset and progression. Our recent work demonstrates that Six1 overexpression in human breast cancer cell lines is sufficient to induce epithelial-to-mesenchymal transition (EMT) and metastasis. Importantly, Six1-induced EMT and metastasis is dependent on TGF–β signaling. The TGF-β pathway plays a dual role in cancer, acting as a tumor suppressor in early lesions, but enhancing metastatic spread in more advanced tumors. Our previous work indicated that Six1 may be a critical mediator of the switch in TGF-β signaling from tumor suppressive to tumor promotional. However, the mechanism by which Six1 impinges on the TGF-β pathway was, until now, unclear. In this work, we identify the TGF-β type I receptor (TβRI) as a target of Six1 and a critical effector of Six1-induced TGF-β signaling and EMT. We demonstrate that Six1-induced upregulation of TβRI is both necessary and sufficient to activate TGF-β signaling and induce properties of EMT. Interestingly, increased TβRI expression is not sufficient to induce experimental metastasis, providing in vivo evidence that Six1 overexpression is required to switch TGF-β signaling to the pro-metastatic phenotype, and demonstrating that induction of EMT is not sufficient to induce experimental metastasis. Together, these results demonstrate a novel mechanism for the activation of TGF-β signaling, identify TβRI as a new target of Six1, and implicate Six1 as a determinant of TGF-β function in breast cancer.