Activation of Notch1 signaling is required for β-catenin-mediated human primary melanoma progression
Activation of Notch1 signaling is required for β-catenin-mediated human primary melanoma progression
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DOI：
10.1172/jci25001
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发表时间：
2005-11-01
影响因子：
15.9
通讯作者：
Liu, ZJ
中科院分区：
文献类型：
--
作者：
Balint, K;Xiao, M;Liu, ZJ
Noch是一种高度保守的跨膜受体，决定细胞的命运。Notch信号指的是Notch胞内区的裂解、转位到细胞核，以及随后靶基因转录的激活。Notch信号在几种癌症中的作用是众所周知的，但它在黑色素瘤中的作用尚不清楚。在这里，我们展示了Notch1通路在人类黑色素瘤中被激活。阻断Notch信号通路可抑制原代黑色素瘤细胞的生长，而Notch1通路的结构性激活可促进原代黑色素瘤细胞的生长，但对转移性黑色素瘤细胞几乎没有影响。Notch1信号的激活使原代黑色素瘤细胞获得转移能力。此外，Notch1对原代黑色素瘤细胞的致癌作用是由β-连环蛋白介导的，该蛋白在Notch1激活后上调。抑制β-连环蛋白的表达逆转了Notch1促进的肿瘤生长和转移。因此，我们的数据表明，Notch1信号在促进原发黑色素瘤的进展中具有β-连环素依赖的、阶段特异性的作用。
Notch is a highly conserved transmembrane receptor that determines cell fate. Notch signaling denotes cleavage of the Notch intracellular domain, its translocation to the nucleus, and subsequent activation of target gene transcription. Involvement of Notch signaling in several cancers is well known, but its role in melanoma remains poorly characterized. Here we show that the Notch1 pathway is activated in human melanoma. Blocking Notch signaling suppressed whereas constitutive activation of the Notch1 pathway enhanced primary melanoma cell growth both in vitro and in vivo yet had little effect on metastatic melanoma cells. Activation of Notch1 signaling enabled primary melanoma cells to gain metastatic capability. Furthermore, the oncogenic effect of Notch1 on primary melanoma cells was mediated by beta-catenin, which was upregulated following Notch1 activation. Inhibiting beta-catenin expression reversed Notch1-enhanced tumor growth and metastasis. Our data therefore suggest a beta-catenin-dependent, stage-specific role for Notch1 signaling in promoting the progression of primary melanoma.