TWIST1 is an ERK1/2 effector that promotes invasion and regulates MMP-1 expression in human melanoma cells.
TWIST1 is an ERK1/2 effector that promotes invasion and regulates MMP-1 expression in human melanoma cells.
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DOI：
10.1158/0008-5472.can-12-1033
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发表时间：
2012-12-15
期刊：
影响因子：
11.2
通讯作者：
Aplin AE
中科院分区：
文献类型：
--
作者：
Weiss MB;Abel EV;Mayberry MM;Basile KJ;Berger AC;Aplin AE
肿瘤细胞通常利用发育过程以进展为晚期疾病。E-box转录因子TWIST 1对发育中的神经嵴中的上皮-间充质转化和细胞迁移至关重要。在源自神经嵴细胞谱系的黑色素瘤中，TWIST 1表达增强与更差的临床预后有关。然而，TWIST1表达的潜在机制以及异常TWIST1水平是否促进黑色素瘤进展的步骤仍然未知。在这里，我们报告说，TWIST 1 mRNA/蛋白表达升高依赖于ERK 1/2信号，这是在大多数黑色素瘤的过度活跃。我们表明，TWIST 1蛋白水平在从侵袭性转移前阶段肿瘤产生的黑色素瘤细胞系中特别高。此外，TWIST 1表达是必要的，并且足以促进三维模拟真皮条件下通过基质胶和球体生长的侵袭。球状体生长的改变不是由于细胞死亡、细胞周期谱或EMT蛋白质改变的结果。重要的是，我们确定基质金属蛋白酶-1（MMP-1）作为TWIST 1的一个新的下游靶点。我们已经确定TWIST 1以剂量依赖性方式作为过度活跃的ERK 1/2信号传导和MMP-1转录调节之间的介导剂。总之，这些研究从机制上证明了ERK 1/2、TWIST 1和MMP-1之间以前未被认识到的相互作用，这在黑素瘤向转移的进展中可能是重要的。
Tumor cells often utilize developmental processes in order to progress towards advanced disease. The E-box transcription factor TWIST1 is essential to epithelial-mesenchymal transition and cell migration in the developing neural crest. In melanoma, which derives from the neural crest cell lineage, enhanced TWIST1 expression has been linked to worse clinical prognosis. However, mechanisms underlying TWIST1 expression and whether aberrant TWIST1 levels promote steps in melanoma progression remain unknown. Here, we report that elevated TWIST1 mRNA/protein expression is dependent on ERK1/2 signaling, which is hyperactive in the majority of melanomas. We show that TWIST1 protein levels are especially high in melanoma cell lines generated from invasive, pre-metastatic stage tumors. Furthermore, TWIST1 expression is required and sufficient to promote invasion through Matrigel and spheroid outgrowth in three-dimensional dermal-mimetic conditions. Alterations to spheroid outgrowth were not as a result of altered cell death, cell cycle profile, or paradigm EMT protein changes. Importantly, we identify matrix metalloproteinase-1 (MMP-1) as a novel downstream target of TWIST1. We have determined that TWIST1 acts, in a dose-dependent manner, as a mediator between hyperactive ERK1/2 signaling and regulation of MMP-1 transcription. Together, these studies mechanistically demonstrate a previously unrecognized interplay between ERK1/2, TWIST1, and MMP-1 which is likely significant in the progression of melanoma towards metastasis.