A miR-130a-YAP positive feedback loop promotes organ size and tumorigenesis.
A miR-130a-YAP positive feedback loop promotes organ size and tumorigenesis.
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miR-130a-YAP正反馈环促进器官大小和肿瘤发生
DOI：
10.1038/cr.2015.98
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发表时间：
2015-09
期刊：
影响因子：
44.1
通讯作者：
Zhao B
中科院分区：
文献类型：
--
作者：
Shen S;Guo X;Yan H;Lu Y;Ji X;Li L;Liang T;Zhou D;Feng XH;Zhao JC;Yu J;Gong XG;Zhang L;Zhao B
器官大小的确定是生物学中最有趣的未解之谜之一。Hippo通路中主要效应子和转录辅激活因子雅普的异常激活导致发育中器官的急剧增大，并成为许多人类癌症中肿瘤发生的基础。然而，在器官大小控制期间如何实现稳健的雅普激活仍然是难以捉摸的。在这里，我们报告说，雅普信号是通过一个新的microRNA依赖性的正反馈回路。由雅普直接诱导的miR-130 a可有效抑制雅普活性抑制剂VGLL 4，从而放大雅普信号。抑制miR-130 a逆转了Hippo通路失活诱导的肝脏体积增大，并阻断了YAP诱导的肿瘤发生。此外，果蝇海马途径靶标bantam通过抑制VGLL 4同源物SdBP/Tgi在功能上模拟miR-130 a。这些发现揭示了Hippo通路在大小控制和肿瘤发生中的鲁棒性的进化上保守的正反馈机制。
Organ size determination is one of the most intriguing unsolved mysteries in biology. Aberrant activation of the major effector and transcription co-activator YAP in the Hippo pathway causes drastic organ enlargement in development and underlies tumorigenesis in many human cancers. However, how robust YAP activation is achieved during organ size control remains elusive. Here we report that the YAP signaling is sustained through a novel microRNA-dependent positive feedback loop. miR-130a, which is directly induced by YAP, could effectively repress VGLL4, an inhibitor of YAP activity, thereby amplifying the YAP signals. Inhibition of miR-130a reversed liver size enlargement induced by Hippo pathway inactivation and blocked YAP-induced tumorigenesis. Furthermore, the Drosophila Hippo pathway target bantam functionally mimics miR-130a by repressing the VGLL4 homolog SdBP/Tgi. These findings reveal an evolutionarily conserved positive feedback mechanism underlying robustness of the Hippo pathway in size control and tumorigenesis.