Active Notch1 confers a transformed phenotype to primary human melanocytes.
Active Notch1 confers a transformed phenotype to primary human melanocytes.
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主动Notch1将转化的表型赋予原代人黑色素细胞。
DOI：
10.1158/0008-5472.can-08-3767
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发表时间：
2009-07-01
期刊：
影响因子：
11.2
通讯作者：
Herlyn M
中科院分区：
文献类型：
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作者：
Pinnix CC;Lee JT;Liu ZJ;McDaid R;Balint K;Beverly LJ;Brafford PA;Xiao M;Himes B;Zabierowski SE;Yashiro-Ohtani Y;Nathanson KL;Bengston A;Pollock PM;Weeraratna AT;Nickoloff BJ;Pear WS;Capobianco AJ;Herlyn M
N-Ras 和 B-Raf 激活突变的盛行凸显了 MAPK 信号在黑色素瘤中的重要性；然而，该途径抑制剂的临床开发基本上无效，这表明替代癌基因也可能促进黑色素瘤。 Notch 是一个有趣的候选者，仅与黑色素瘤的发生和进展相关。对激活的Notch对人类黑素细胞的肿瘤引发作用进行全面评估将澄清越来越多的相关证据，并可能为一种无法治疗的疾病确定一个新的靶点。对大量细胞系和患者病变的分析表明，黑色素瘤中的 Notch 活性明显高于未转化的黑色素瘤。利用组成型活性、截短的 Notch 转基因构建体 (NIC) 来确定 Notch 激活是黑素细胞转化中的“驱动”事件，还是与黑色素瘤进展相关的“乘客”事件。 NIC 感染的黑色素细胞表现出增强的增殖能力和更类似于黑色素瘤的生物学特征，例如细胞粘附和迁移失调。基因表达分析支持了这些观察结果，并有助于鉴定 MCAM（一种与恶性表型获得相关的粘附分子）作为 Notch 反式激活的直接靶标。 NIC 阳性黑色素细胞以克隆密度生长，在有限的培养基条件下增殖，并且还表现出不依赖贴壁的生长，这表明单独的 Notch 是人类黑色素细胞中的转化癌基因，这种现象以前从未在任何黑色素瘤癌基因中描述过；这一新信息为了解黑色素瘤的基本流行病学提供了宝贵的见解，并为药物干预这种致命疾病开辟了新的可能性。
The importance of MAPK signaling in melanoma is underscored by the prevalence of activating mutations in N-Ras and B-Raf; yet, clinical development of inhibitors of this pathway has been largely ineffective, suggesting that alternative oncogenes may also promote melanoma. Notch is an interesting candidate that has only been correlated with melanoma development and progression; a thorough assessment of tumor-initiating effects of activated Notch on human melanocytes would clarify the mounting correlative evidence and perhaps identify a novel target for an otherwise untreatable disease. Analysis of a substantial panel of cell lines and patient lesions demonstrated that Notch activity is significantly higher in melanomas than their non-transformed counterparts. The use of a constitutively-active, truncated Notch transgene construct (NIC) was exploited to determine if Notch activation is a ‘driving’ event in melanocytic transformation or instead a ‘passenger’ event associated with melanoma progression. NIC-infected melanocytes displayed increased proliferative capacity and biological features more reminiscent of melanoma such as dysregulated cell adhesion and migration. Gene expression analyses supported these observations and aided in the identification of MCAM, an adhesion molecule associated with acquisition of the malignant phenotype, as a direct target of Notch transactivation. NIC-positive melanocytes grew at clonal density, proliferated in limiting media conditions, and also exhibited anchorage-independent growth suggesting that Notch, alone, is a transforming oncogene in human melanocytes, a phenomenon not previously described for any melanoma oncogene; this new information yields valuable insight into the basic epidemiology of melanoma and launches a realm of possibilities for drug intervention in this deadly disease.