Notch1 signaling promotes primary melanoma progression by activating mitogen-activated protein kinase/phosphatidylinositol 3-kinase-Akt pathways and up-regulating N-cadherin expression
Notch1 signaling promotes primary melanoma progression by activating mitogen-activated protein kinase/phosphatidylinositol 3-kinase-Akt pathways and up-regulating N-cadherin expression
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DOI：
10.1158/0008-5472.can-05-3589
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发表时间：
2006-04-15
期刊：
影响因子：
11.2
通讯作者：
Herlyn, M
中科院分区：
文献类型：
--
作者：
Liu, ZJ;Xiao, M;Herlyn, M
Notch受体介导的细胞信号传导导致细胞生长、存活和分化的协调调节。异常Notch激活与多种人类肿瘤有关。在这里，我们表明，Notch 1信号驱动的垂直生长期（VGP）的原发性黑色素瘤朝着一个更具侵略性的表型。Notch 1细胞内结构域的异位表达对Notch 1的组成性激活使VGP原代黑色素瘤细胞系能够在体外以不依赖血清和生长因子的方式增殖，并在体内以具有转移活性的方式更积极地生长。Notch 1激活也增强了肿瘤细胞的生存培养时，三维球体。Notch信号传导的这种作用是由促分裂原活化蛋白激酶（MAPK）和Akt途径的活化介导的。在Notch 1途径激活后，这两种途径在黑素瘤细胞中被激活。MAPK或磷脂酰肌醇3-激酶（PI 3 K）-Akt通路的抑制逆转Notch 1信号诱导的肿瘤细胞生长。此外，Notch 1的促生长作用依赖于masterpiec-like 1。我们进一步表明，Notch 1激活增加肿瘤细胞粘附和上调N-钙粘蛋白的表达。我们的数据显示了MAPK/PI 3 K-Akt通路活性和N-cadherin表达通过Notch通路的调节，并为Notch信号传导促进原发性黑色素瘤进展提供了机制基础。
Cellular signaling mediated by Notch receptors results in coordinated regulation of cell growth, survival, and differentiation. Aberrant Notch activation has been linked to a variety of human neoplasms. Here, we show that Notch1 signaling drives the vertical growth phase (VGP) of primary melanoma toward a more aggressive phenotype. Constitutive activation of Notch1 by ectopic expression of the Notch1 intracellular domain enables VGP primary melanoma cell lines to proliferate in a serum-independent and growth factor-independent manner in vitro and to grow more aggressively with metastatic activity in vivo. Notch1 activation also enhances tumor cell survival when cultured as three-dimensional spheroids. Such effects of Notch signaling are mediated by activation of the mitogen-activated protein kinase (MAPK) and Akt pathways. Both pathways are activated in melanoma cells following Notch1 pathway activation. Inhibition of either the MAPK or the phosphatidylinositol 3-kinase (PI3K)-Akt pathway reverses the Notch1 signaling-induced tumor cell growth. Moreover, the growth-promoting effect of Notch1 depends on mastermind-like 1. We further showed that Notch1 activation increases tumor cell adhesion and up-regulates N-cadherin expression. Our data show regulation of MAPK/PI3K-Akt pathway activities and expression of N-cadherin by the Notch pathway and provide a mechanistic basis for Notch signaling in the promotion of primary melanoma progression.