Notch-1 signaling facilitates survivin expression in human non-small cell lung cancer cells
Notch-1 signaling facilitates survivin expression in human non-small cell lung cancer cells
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Notch-1信号传导促进人非小细胞肺癌细胞中生存素的表达
DOI：
10.4161/cbt.11.1.13730
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发表时间：
2011-01-01
影响因子：
3.6
通讯作者：
Wang, Xiaojing
中科院分区：
文献类型：
--
作者：
Chen, Yuqing;Li, Dianming;Wang, Xiaojing
Notch激活的致癌潜力在许多情况下被观察到，包括肺肿瘤发生，但相关的分子调控机制尚未完全确定。研究表明，缺氧是多种肿瘤发生发展的主要刺激因素之一。本研究旨在检测缺氧对Notch-1信号通路的激活及其对人肺癌中Survivin表达的影响。Western-blot和PCR分析显示，在人非小细胞肺癌（NSCLC）细胞系A549中，缺氧通过上调Notch-1及其胞内结构域（N1ICD）激活Notch-1信号传导。缺氧时N1ICD的重要靶分子Hes-1的活性也增加。有趣的是，通过γ-分泌酶抑制剂或小干扰RNA（siRNA）阻断Notch-1途径抑制了存活素表达。相反，N1ICD激活Notch-1信号或Jagged1配体刺激增强A549细胞中的存活素水平。值得注意的是，HIF-1 α与Notch-1信号传导合作，通过其与N1ICD的直接关联来增加Survivin的表达，从而加速Survivin的转录。总之，我们的研究结果表明，Notch-1信号参与了肺癌细胞中Survivin表达的上调，HIF-1 α对此有协同作用。
The oncogenic potential of Notch activation is observed in many instances including lung tumorigenesis, but the associated molecular regulatory mechanism has not been thoroughly defined. It has been demonstrated that hypoxia can act as one of the major stimuli in the progression of many types of tumorigenesis. This study was designed to examine the activation of Notch-1 signaling by hypoxia and its contribution to survivin expression in human lung carcinomas. Western-blot and PCR analysis showed that Notch-1 signaling is activated by hypoxia in the human non-small cell lung cancer (NSCLC) cell line, A549, through the upregulation of Notch-1, along with its intracellular domain (N1ICD). The activity of Hes-1, a crucial target molecule of N1ICD, was also increased under hypoxia. Interestingly, blockade of the Notch-1 pathway by a γ-secretase inhibitor or small interfering RNA (siRNA) inhibited survivin expression. Conversely, activation of Notch-1 signaling by N1ICD or stimulation with the Jagged1 ligand enhanced survivin levels in A549 cells. Notably, HIF-1α cooperated with Notch-1 signaling to increase survivin expression through its direct association with N1ICD, consequently accelerating survivin transcription. Overall, our findings suggest that Notch-1 signaling is involved in the upregulation of survivin expression in lung cancer cells, which is synergized by HIF-1α.