Yes-Associated Protein (YAP) Modulates Oncogenic Features and Radiation Sensitivity in Endometrial Cancer

Masahiro Tsujiura,Radhika Gogoi,Marius Sudol,Hanna G Kaspar,John Nash,David J Carey,Virginia Mazack,Hong Wanjin

doi:10.1371/journal.pone.0100974

Abstract

BackgroundYes-associated protein (YAP) is a transcriptional co-activator and regulates cell proliferation and apoptosis. We investigated the clinical and biological significance of YAP in endometrial cancer (EMCA).MethodsYAP expression in 150 primary tumor tissues from patients with EMCA was evaluated by immunohistochemistry and its association with clinicopathological data was assessed. The biological functions of YAP were determined in EMCA cell lines through knockdown/overexpression of YAP. The role of YAP in modulating radiation sensitivity was also investigated in EMCA cells.ResultsIncreased nuclear YAP expression was significantly associated with higher grade, stage, lympho-vascular space invasion, postoperative recurrence/metastasis and overall survival in estrogen mediated EMCA, called type 1 cancer (p = 0.019, = 0.028, = 0.0008, = 0.046 and = 0.015, respectively). In multivariate analysis, nuclear YAP expression was confirmed as an independent prognostic factor for overall survival in type 1 EMCA. YAP knockdown by siRNA resulted in a significant decrease in cell proliferation (p<0.05), anchorage-dependent growth (p = 0.015) and migration/invasion (p<0.05), and a significant increase in the number of cells in G0/G1 phase (p = 0.002). Conversely, YAP overexpression promoted cell proliferation. Clonogenic assay demonstrated enhanced radiosensitivity by approximately 36% in YAP inhibited cells.ConclusionsSince YAP functions as a transcriptional co-activator, its differential localization in the nucleus of cancer cells and subsequent impact on cell proliferation could have important consequences with respect to its role as an oncogene in EMCA. Nuclear YAP expression could be useful as a prognostic indicator or therapeutic target and predict radiation sensitivity in patients with EMCA.

Highlights

Endometrial cancer (EMCA) is the fourth most common cancer and the most common gynecologic cancer in American women, with approximately 8200 deaths and 49500 new cases in the United States in 2013 [1]
Yes-associated protein (YAP) protein expression in primary endometrial cancer (EMCA) tissues To determine whether YAP is expressed in human EMCA, YAP protein expression in primary EMCA tissues was assessed by immunohistochemistry
Type 2 EMCA had higher stage, higher frequency of lympho-vascular space invasion (LVSI) and postoperative metastasis/recurrence, and higher nuclear YAP expression compared with type 1 EMCA

Summary

Introduction

Endometrial cancer (EMCA) is the fourth most common cancer and the most common gynecologic cancer in American women, with approximately 8200 deaths and 49500 new cases in the United States in 2013 [1]. While women with EMCA generally have a good prognosis with 81.5% 5-year survival (2003–2009), the incidence and death rate of EMCA have continued to rise on average 1.1% and 0.4% respectively each year over the last 10 years [2]. Recent increases in the incidence of endometrial cancer rates have been considered largely attributed to the obesity epidemic [3]. Improvements in diagnostic techniques and peri-operative management have resulted in an increase in the early detection of EMCA and favorable prognosis, women diagnosed with advanced or recurrent disease have much worse survival rates and limited adjuvant treatment options. We investigated the clinical and biological significance of YAP in endometrial cancer (EMCA)

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Conclusion