NF-κB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression
NF-κB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression
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DOI：
10.1172/jci200421358
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发表时间：
2004-08-01
影响因子：
15.9
通讯作者：
Wirth, T
中科院分区：
文献类型：
--
作者：
Huber, MA;Azoitei, N;Wirth, T
转录因子NF-κ B在一系列人类癌症中被激活，并且被认为促进肿瘤发生，主要是由于其保护转化细胞免于凋亡的能力。为了研究NF-kappaB在上皮可塑性和转移中的作用，我们利用了一个充分表征的体外/体内乳腺癌发生模型，该模型依赖于Ha-Ras癌蛋白和TGF-β的协作。我们发现IKK-2/IkappaB α/NF-kappaB通路是诱导和维持上皮-间充质转化（EMT）所必需的。抑制NF-kappaB信号传导阻止Ras转化的上皮细胞中的EMT，而即使在没有TGF-β的情况下，该途径的激活也促进向间充质表型的转变。此外，抑制间充质细胞中的NF-κ B活性导致EMT逆转，表明NF-κ B对于EMT的诱导和维持是必不可少的。与EMT对侵袭的重要性一致，在小鼠模型系统中，NF-κ B活性的阻断消除了乳腺上皮细胞的转移潜力。总的来说，这些数据提供了证据的NF-κ B在乳腺癌进展的不同步骤中的重要作用，并表明Ras和TGF-β依赖性信号通路在晚期肿瘤发生中的合作关键取决于NF-κ B活性。
The transcription factor NF-kappaB is activated in a range of human cancers and is thought to promote tumorigenesis, mainly due to its ability to protect transformed cells from apoptosis. To investigate the role of NF-kappaB in epithelial plasticity and metastasis, we utilized a well-characterized in vitro/in vivo model of mammary carcinogenesis that depends on the collaboration of the Ha-Ras oncoprotein and TGF-beta. We show here that the IKK-2/IkappaBalpha/NF-kappaB pathway is required for the induction and maintenance of epithelial-mesenchymal transition (EMT). Inhibition of NF-kappaB signaling prevented EMT in Ras-transformed epithelial cells, while activation of this pathway promoted the transition to a mesenchymal phenotype even in the absence of TGF-beta. Furthermore, inhibition of NF-kappaB activity in mesenchymal cells caused a reversal of EMT, suggesting that NF-kappaB is essential for both the induction and maintenance of EMT. In line with the importance of EMT for invasion, blocking of NF-kappaB activity abrogated the metastatic potential of mammary epithelial cells in a mouse model system. Collectively, these data provide evidence of an essential role for NF-kappaB during distinct steps of breast cancer progression and suggest that the cooperation of Ras- and TGF-beta-dependent signaling pathways in late-stage tumorigenesis depends critically on NF-kappaB activity.