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

Shuying Shen; Xiaocan Guo; Huan Yan; Yi Lu; Xinyan Ji; Li Li; Tingbo Liang; Dawang Zhou; Xin-Hua Feng; Jonathan C Zhao; Jindan Yu; Xing-Guo Gong; Lei Zhang; Bin Zhao

doi:10.1038/cr.2015.98

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

Cell Res. 2015 Sep;25(9):997-1012. doi: 10.1038/cr.2015.98. Epub 2015 Aug 14.

Authors

Shuying Shen^{1

2}, Xiaocan Guo¹, Huan Yan¹, Yi Lu³, Xinyan Ji¹, Li Li⁴, Tingbo Liang⁵, Dawang Zhou⁶, Xin-Hua Feng¹, Jonathan C Zhao⁷, Jindan Yu⁷, Xing-Guo Gong², Lei Zhang³, Bin Zhao¹

Affiliations

¹ Life Sciences Institute and Innovation Center for Cell Signaling Network Hangzhou, Zhejiang 310058, China.
² Institute of Biochemistry, College of Life Science Hangzhou, Zhejiang 310058, China.
³ State 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.
⁴ Institute of Aging Research, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
⁵ Department 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.
⁶ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
⁷ Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acyltransferases
Adaptor Proteins, Signal Transducing / antagonists & inhibitors
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Base Sequence
Carcinogenesis*
Cell Line, Tumor
Cell Proliferation
Cysteine-Rich Protein 61 / antagonists & inhibitors
Cysteine-Rich Protein 61 / genetics
Cysteine-Rich Protein 61 / metabolism
Drosophila / metabolism
Drosophila Proteins / metabolism
Hep G2 Cells
Humans
Male
Mice
Mice, Inbred ICR
Mice, Nude
MicroRNAs / antagonists & inhibitors
MicroRNAs / metabolism*
Organ Size / genetics
Phosphoproteins / antagonists & inhibitors
Phosphoproteins / genetics
Phosphoproteins / metabolism*
Sequence Alignment
Signal Transduction
Transcription Factors / antagonists & inhibitors
Transcription Factors / genetics
Transcription Factors / metabolism
Transplantation, Heterologous
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
CCN1 protein, human
Cysteine-Rich Protein 61
Drosophila Proteins
MIRN130 microRNA, human
MicroRNAs
Phosphoproteins
Transcription Factors
VGLL4 protein, human
YAP-Signaling Proteins
YAP1 protein, human
Acyltransferases
TAFAZZIN protein, human