Restore the brake on tumor progression.
Restore the brake on tumor progression.
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恢复对肿瘤进展的抑制
DOI：
10.1016/j.bcp.2017.04.003
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发表时间：
2017-08-15
影响因子：
5.8
通讯作者：
Yang ZJ
中科院分区：
文献类型：
--
作者：
Gordon RE;Zhang L;Yang ZJ
Sonic hedgehog（Shh）信号在调节正常发育中起着关键作用。由转录因子Gli3介导的负反馈机制可以精细调节Shh信号传导，从而对正常发育过程进行严格控制。Shh信号的过度激活通常导致许多人类恶性肿瘤，包括基底细胞癌和髓母细胞瘤（MB）。然而，肿瘤细胞如何维持Shh信号的异常激活仍然没有完全理解。我们最近发现，在MB形成过程中，肿瘤细胞表达Nestin，一种VI型中间丝蛋白，通过消除Gli3的负反馈来维持不受控制的Shh信号。因此，Nestin的表达是MB形成的必要步骤。这些发现强调了巢蛋白在调节Shh信号传导中的新功能，以及在MB肿瘤发生中被破坏的负反馈机制的重要作用。此外，通过抑制巢蛋白表达来恢复内在负反馈代表了治疗MB以及其他Shh信号传导相关恶性肿瘤的有希望的方法。Nestin的表达是Shh型髓母细胞瘤发生所必需的。为了实现这一目标，巢蛋白通过消除Gli3介导的负反馈机制来增强髓母细胞瘤细胞中的Shh信号。
Sonic hedgehog (Shh) signaling plays a key role in regulating normal development. The negative feedback mechanism mediated by the transcriptional factor, Gli3, acts to finely tune Shh signaling, providing tight control of normal developmental processes. Hyperactivation of Shh signaling often leads to many human malignancies, including basal cell carcinoma and medulloblastoma (MB). However, how tumor cells sustain the aberrant activation of Shh signaling is still not completely understood. We recently revealed that during MB formation, tumor cells express Nestin, a type VI intermediate filament protein, which maintains uncontrolled Shh signaling by abolishing negative feedback by Gli3. Therefore, Nestin expression is a necessary step for MB formation. These findings highlight the novel function of Nestin in regulating Shh signaling, as well as the important role of a disrupted negative feedback mechanism in MB tumorigenesis. Further, restoration of the intrinsic negative feedback by repressing Nestin expression represents a promising approach to treat MB as well as other Shh signaling associated malignancies. Nestin expression is indispensable for Shh type medulloblastoma tumorigenesis. To achieve this, Nestin augments Shh signaling in medulloblastoma cells by abolishing Gli3-mediated negative feedback mechanism.