Regulation of the embryonic morphogen Nodal by Notch4 facilitates manifestation of the aggressive melanoma phenotype.
Regulation of the embryonic morphogen Nodal by Notch4 facilitates manifestation of the aggressive melanoma phenotype.
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DOI：
10.1158/0008-5472.can-10-0705
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发表时间：
2010-12-15
期刊：
影响因子：
11.2
通讯作者：
Hendrix MJ
中科院分区：
文献类型：
--
作者：
Hardy KM;Kirschmann DA;Seftor EA;Margaryan NV;Postovit LM;Strizzi L;Hendrix MJ
转移性黑色素瘤是一种侵袭性皮肤癌，预后不良。转移性黑色素瘤中胚胎形态原Nodal的再活化先前已被证明可调节这些肿瘤细胞的侵袭行为。在脊椎动物发育早期左右不对称的建立过程中，Nodal的表达受到Notch信号通路的特异性调节。我们假设在黑色素瘤中可能重新建立Notch和Nodal之间的类似关系。在这项研究中，我们研究了Notch和Nodal通路之间的串扰是否可以解释Nodal在侵袭性转移性黑色素瘤细胞中的重新激活。我们证明了在侵袭性黑色素瘤细胞系MV3中Notch和Nodal信号传导之间的分子联系，通过RBPJ依赖性Nodal增强子元件的活性。我们在多种侵袭性细胞系中显示Notch4和Nodal表达之间的精确相关性，但在侵袭性差的细胞系中没有。令人惊讶的是，Notch4是Nodal在侵袭性细胞中表达所特异性需要的，并且在细胞生长的平衡和侵袭性表型的调节中起着至关重要的作用。此外，Notch4在体外血管生成拟态和锚定非依赖性生长中的功能部分归因于Notch4对Nodal的调节。这项研究确定了Notch4和Nodal之间的串扰在转移性黑色素瘤中的重要作用，将Notch4置于Nodal的上游，并为黑色素瘤治疗提供了潜在的分子靶点。
Metastatic melanoma is an aggressive skin cancer associated with poor prognosis. The reactivation of the embryonic morphogen Nodal in metastatic melanoma has previously been shown to regulate the aggressive behavior of these tumor cells. During the establishment of left-right asymmetry in early vertebrate development, Nodal expression is specifically regulated by a Notch signaling pathway. We hypothesize that a similar relationship between Notch and Nodal may be re-established in melanoma. In this study, we investigate if cross-talk between the Notch and Nodal pathways can explain the reactivation of Nodal in aggressive metastatic melanoma cells. We demonstrate a molecular link between Notch and Nodal signaling in the aggressive melanoma cell line MV3, via the activity of an RBPJ-dependent Nodal enhancer element. We show a precise correlation between Notch4 and Nodal expression in multiple aggressive cell lines, but not poorly aggressive cell lines. Surprisingly, Notch4 is specifically required for expression of Nodal in aggressive cells, and plays a vital role in the balance of cell growth and in the regulation of the aggressive phenotype. In addition, Notch4 function in vasculogenic mimicry and anchorage independent growth in vitro is due in part to Notch4 regulation of Nodal. This study identifies an important role for cross-talk between Notch4 and Nodal in metastatic melanoma, placing Notch4 upstream of Nodal, and offers a potential molecular target for melanoma therapy.