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首页> 外文期刊>Oncogene >Constitutive activation of Notch3 inhibits terminal epithelial differentiation in lungs of transgenic mice
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Constitutive activation of Notch3 inhibits terminal epithelial differentiation in lungs of transgenic mice

机译：Notch3的组成性激活抑制转基因小鼠肺的终末上皮细胞分化

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摘要

Notch3 is a transmembrane receptor and a member of the Notch signaling pathway essential for cellular differentiation in a variety of developing tissues in both invertebrates and vertebrates. Emerging data support the role of the Notch signaling pathway in tumorigenesis. We have previously demonstrated the expression of Notch3 in a subset of lung adenocarcinomas. To further elucidate the role of Notch3 in development of lung cancer, we established a transgenic mouse model in which the intracellular domain of Notch3 is expressed using the surfactant protein C promoter/enhancer. Constitutive expression of Notch3 in the peripheral epithelium in the developing lung resulted in altered lung morphology and delayed development, leading to perinatal lethality in these transgenic mice. Cell-specific markers and electron microscopy examination showed that the majority of the epithelial cells are undifferentiated, with some maturation of type II pneumocytes. No type I alveolar cells were evident. Metaplasia of undifferentiated cells in the terminal airways was also observed. Although the mice did not live long enough to assess tumor development, these findings demonstrate that ectopic expression of Notch3 in airway epithelium potentially contributes to the multistep evolution of lung cancer through the inhibition of terminal differentiation.
机译：Notch3是跨膜受体，是在无脊椎动物和脊椎动物的各种发育组织中细胞分化所必需的Notch信号通路的成员。新兴数据支持Notch信号通路在肿瘤发生中的作用。我们以前已经证明了Notch3在一部分肺腺癌中的表达。为了进一步阐明Notch3在肺癌发生中的作用，我们建立了一个转基因小鼠模型，其中使用表面活性剂蛋白C启动子/增强子表达Notch3的胞内结构域。 Notch3在发育中的肺的外周上皮中的组成性表达导致肺形态改变和发育延迟，导致这些转基因小鼠的围产期致死率。细胞特异性标记物和电子显微镜检查显示，大多数上皮细胞未分化，并且II型肺细胞有些成熟。没有明显的I型肺泡细胞。还观察到终末呼吸道中未分化细胞的化生。尽管小鼠的寿命不足以评估肿瘤的发展，但这些发现表明，Notch3在气道上皮中的异位表达可能通过抑制终末分化而促进肺癌的多步进化。

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