MiR-663 inhibits radiation-induced bystander effects by targeting TGFB1 in a feedback mode
MiR-663 inhibits radiation-induced bystander effects by targeting TGFB1 in a feedback mode
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MiR-663 通过以反馈模式靶向 TGFB1 抑制辐射引起的旁观者效应
DOI：
10.4161/rna.34345
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发表时间：
2014-09-01
期刊：
影响因子：
4.1
通讯作者：
Zhou, Guangming
中科院分区：
文献类型：
--
作者：
Hu, Wentao;Xu, Shuai;Zhou, Guangming
辐射诱导的旁观者效应（里贝）的机制在过去的二十年里得到了广泛的研究。虽然有相当多的报道表明，细胞因子如TGF-1的诱导直接照射细胞内，并在介导的旁观者效应中发挥关键作用，很少有人知道发生在旁观者细胞的信号通路。因此，为什么里贝电子束信号不能无限传输的关键问题仍然不清楚。在本研究中，我们发现，miR-663，一种放射敏感的microRNA，参与调节直接照射和旁观者细胞的生物效应，通过其靶向TGF-1。在直接照射的细胞中，miR-663下调，而TGFB 1上调。另一方面，旁观者细胞中miR-663和TGFB 1的调节谱被逆转，其中miR-663表达升高，并导致TGF-1下调。进一步的研究表明，miR-663与TGFB 1直接相互作用，并通过其与核心调控序列的结合，抑制TGFB 1的表达。基于这些结果，我们提出miR-663以反馈模式抑制里贝的增殖，其中直接照射细胞中减少的miR-663诱导TGF-1导致旁观者细胞中miR-663水平增加。miR-663的上调反过来抑制TGF-1的表达并限制旁观者信号的进一步传递。
The mechanisms of radiation-induced bystander effects (RIBE) have been investigated intensively over the past two decades. Although quite a few reports demonstrated that cytokines such as TGF-1 are induced within the directly irradiated cells and play critical roles in mediating the bystander effects, little is known about the signaling pathways that occur in bystander cells. The crucial question as to why RIBE signals cannot be infinitely transmitted, therefore, remains unclear. In the present study, we showed that miR-663, a radiosensitive microRNA, participates in the regulation of biological effects in both directly irradiated and bystander cells via its targeting of TGF-1. MiR-663 was downregulated, while TGFB1 was upregulated in directly irradiated cells. The regulation profile of miR-663 and TGFB1, on the other hand, was reversed in bystander cells, in which an elevated miR-663 expression was exhibited and led to downregulation of TGF-1. Further studies revealed that miR-663 interacts with TGFB1 directly and that through its binding to the core regulation sequence, miR-663 suppresses the expression of TGFB1. Based on the results, we propose that miR-663 inhibits the propagation of RIBE in a feedback mode, in which the induction of TGF-1 by reduced miR-663 in directly irradiated cells leads to increased level of miR-663 in bystander cells. The upregulation of miR-663 in turn suppresses the expression of TGF-1 and limits further transmission of the bystander signals.