Volume 25, No 9, Sep 2015

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 25 Issue 9, September 2015: 997-1012   |  Open Access

ORIGINAL ARTICLE

A miR-130a-YAP positive feedback loop promotes organ size and tumorigenesis

Shuying Shen^1,2,*, Xiaocan Guo^1,*, Huan Yan¹, Yi Lu⁴, Xinyan Ji¹, Li Li⁵, Tingbo Liang³, Dawang Zhou⁶, Xin-Hua Feng¹, Jonathan C Zhao⁷, Jindan Yu⁷, Xing-Guo Gong², Lei Zhang⁴ and Bin Zhao¹

¹Life Sciences Institute and Innovation Center for Cell Signaling Network Hangzhou, Zhejiang 310058, China
²Institute of Biochemistry, College of Life Science Hangzhou, Zhejiang 310058, China
³Department of Hepatobiliary and Pancreatic Surgery and the Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China
⁴State Key Laboratory of Cell Biology and Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
⁵Institute of Aging Research, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China
⁶State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
⁷Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA Correspondence: Bin Zhao, Tel: 86-571-8820-8545; Fax: 86-571-8898-1336(binzhao@zju.edu.cn)

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.

10.1038/cr.2015.98

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