YAP promotes ovarian cancer cell tumorigenesis and is indicative of a poor prognosis for ovarian cancer patients

Yan Xia; Ting Chang; Yingmei Wang; Yixiong Liu; Wenhui Li; Ming Li; Heng-Yu Fan

doi:10.1371/journal.pone.0091770

YAP promotes ovarian cancer cell tumorigenesis and is indicative of a poor prognosis for ovarian cancer patients

PLoS One. 2014 Mar 12;9(3):e91770. doi: 10.1371/journal.pone.0091770. eCollection 2014.

Authors

Yan Xia¹, Ting Chang², Yingmei Wang³, Yixiong Liu³, Wenhui Li⁴, Ming Li⁵, Heng-Yu Fan¹

Affiliations

¹ Life Sciences Institute and Innovation Center for Cell Biology, Zhejiang University, Hangzhou, China.
² Department of Neurology, Tangdu Hospital, the Fourth Military Medical University, Xi'an, China.
³ Department of Pathology, Xijing Hospital, the Fourth Military Medical University, Xi'an, China.
⁴ Department of Obstetrics and Gynecology, Xijing Hospital, the Fourth Military Medical University, Xi'an, China.
⁵ The Affiliated Guangren Hospital, Xi'an Jiaotong University, Xi'an, China.

Abstract

YAP is a key component of the Hippo signaling pathway and plays a critical role in the development and progression of multiple cancer types, including ovarian cancer. However, the effects of YAP on ovarian cancer development in vivo and its downstream effectors remain uncertain. In this study we found that strong YAP expression was associated with poor ovarian cancer patient survival. Specifically, we showed for the first time that high YAP expression levels were positively correlated with TEAD4 gene expression, and their co-expression was a prognostic marker for poor ovarian cancer survival. Hyperactivation of YAP by mutating its five inhibitory phosphorylation sites (YAP-5SA) increased ovarian cancer cell proliferation, resistance to chemotherapeutic drugs, cell migration, and anchorage-independent growth. In contrast, expression of a dominant negative YAP mutant reversed these phenotypes in ovarian cancer cells both in vitro and in vivo. Our results suggested that YAP caused these effects by promoting an epithelial-to-mesenchymal transition. Thus, YAP promotes ovarian cancer cell growth and tumorigenesis both in vitro and in vivo. Further, high YAP and TEAD4 expression is a prognostic marker for ovarian cancer progression and a potential target for ovarian cancer treatment.

Publication types

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

MeSH terms

Active Transport, Cell Nucleus / drug effects
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Apoptosis / drug effects
Carcinogenesis* / drug effects
Cell Line, Tumor
Cell Movement / drug effects
Cell Nucleus / drug effects
Cell Nucleus / metabolism
Cell Proliferation / drug effects
Cell Transformation, Neoplastic
Cisplatin / pharmacology
DNA-Binding Proteins / metabolism
Drug Resistance, Neoplasm
Female
Gene Expression Regulation, Neoplastic / drug effects
Humans
Mice
Muscle Proteins / metabolism
Ovarian Neoplasms / diagnosis*
Ovarian Neoplasms / metabolism
Ovarian Neoplasms / pathology*
Paclitaxel / pharmacology
Phosphoproteins / metabolism*
Prognosis
TEA Domain Transcription Factors
Transcription Factors / metabolism
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
DNA-Binding Proteins
Muscle Proteins
Phosphoproteins
TEA Domain Transcription Factors
TEAD4 protein, human
Transcription Factors
YAP-Signaling Proteins
YAP1 protein, human
Paclitaxel
Cisplatin

Grants and funding

This study was supported by the National Natural Science Foundation of China (81172473), the National Basic Research Program of China (2011CB944504, 2012CB944403), and Basic Scientific Research Funding of Zhejiang University (2011QN81001). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.