Balint Klara, Xiao Min, Pinnix Chelsea C, Soma Akinobu, Veres Imre, Juhasz Istvan, Brown Eric J, Capobianco Anthony J, Herlyn Meenhard, Liu Zhao-Jun
The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
J Clin Invest. 2005 Nov;115(11):3166-76. doi: 10.1172/JCI25001. Epub 2005 Oct 20.
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.
Notch是一种高度保守的跨膜受体，可决定细胞命运。Notch信号传导指的是Notch细胞内结构域的裂解、其向细胞核的转位以及随后靶基因转录的激活。Notch信号传导参与多种癌症已广为人知，但其在黑色素瘤中的作用仍知之甚少。在此我们表明，Notch1通路在人类黑色素瘤中被激活。阻断Notch信号传导会抑制黑色素瘤细胞生长，而Notch1通路的组成性激活则会增强原发性黑色素瘤细胞在体外和体内的生长，但对转移性黑色素瘤细胞影响不大。Notch1信号传导的激活使原发性黑色素瘤细胞获得转移能力。此外，Notch1对原发性黑色素瘤细胞的致癌作用是由β-连环蛋白介导的，β-连环蛋白在Notch1激活后上调。抑制β-连环蛋白表达可逆转Notch1增强的肿瘤生长和转移。因此，我们的数据表明Notch1信号传导在促进原发性黑色素瘤进展中具有β-连环蛋白依赖性、阶段特异性作用。
