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Activation of YAP1 is associated with poor prognosis and response to taxanes in ovarian cancer.

ABSTRACT: AIM:We aimed to investigate the clinical significance of the activation of Yes-Associated Protein 1 (YAP1), a key downstream effector of Hippo tumor-suppressor pathway, in ovarian cancer. MATERIALS AND METHODS:A gene expression signature reflecting activation of YAP1 was developed from gene expression data of 267 samples from patients with ovarian cancer. A refined ovarian cancer YAP1 signature was validated in an independent ovarian cancer cohort (n=185). Associations between the YAP1 signature and prognosis were assessed using Kaplan-Meier plots, the log-rank test, and a Cox proportional hazards model. RESULTS:We identified a 612-gene expression signature reflecting YAP1 activation in ovarian cancer. In multivariate analysis, the signature was an independent predictor of overall survival (hazard ratio=1.66; 95% confidence interval=1.1 to 2.53; p=0.01). In subset analysis, the signature identified patients likely to benefit from taxane-based adjuvant chemotherapy. CONCLUSION:Activation of YAP1 is significantly associated with prognosis and the YAP1 signature can predict response to taxane-based adjuvant chemotherapy in patients with ovarian cancer.

SUBMITTER: Jeong W

PROVIDER: S-EPMC4082822 | biostudies-other | 2014 Feb

REPOSITORIES: biostudies-other

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Activation of YAP1 is associated with poor prognosis and response to taxanes in ovarian cancer.

Jeong Woojin W Kim Sang-Bae SB Sohn Bo Hwa BH Park Yun-Yong YY Park Eun Sung ES Kim Sang Cheol SC Kim Sung Soo SS Johnson Randy L RL Birrer Michael M Bowtell David S L DSL Mills Gordon B GB Sood Anil A Lee Ju-Seog JS

Anticancer research 20140201 2

<h4>Aim</h4>We aimed to investigate the clinical significance of the activation of Yes-Associated Protein 1 (YAP1), a key downstream effector of Hippo tumor-suppressor pathway, in ovarian cancer.<h4>Materials and methods</h4>A gene expression signature reflecting activation of YAP1 was developed from gene expression data of 267 samples from patients with ovarian cancer. A refined ovarian cancer YAP1 signature was validated in an independent ovarian cancer cohort (n=185). Associations between the ...[more]

PMID: 24511017

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Project description:BackgroundOvarian cancer is the leading cause of gynecologic cancer death in the United States despite effective first-line systemic chemotherapy. Cancer stem cells (CSCs) retain the ability to self-renew and proliferate and may be a means of harboring disease that evades standard treatment strategies. We previously performed a high-throughput screen to assess differential protein expression in ovarian CSCs compared to non-CSCs and observed that Thy-1 was more highly expressed in CSCs. Our primary aim was to validate Thy-1 (CD90) as a cancer stem cell (CSC) marker in epithelial ovarian cancer (EOC), correlate with clinical outcomes, and assess as a potential therapeutic target.ResultsKaplan Meier (KM) Plotter data were correlated with survival outcomes. Quantitative real-time PCR, flow cytometry, and immunoblots assessed RNA and protein expression. Limiting dilution assays assessed self-renewal capacity and proliferation assays assessed proliferative capacity. RNA in-situ hybridization was performed on patient specimens to assess feasibility. Thy-1 (CD90) is more highly expressed in ovarian CSCs than non-CSCs, in EOC compared to benign ovarian epithelium (P < 0.001), and is highest in serous EOC (P < 0.05). Serous ovarian cancers with high Thy-1 expression have poorer outcomes (median PFS 15.8 vs. 18.3 months, P = 0 < 0.001; median OS 40.1 v. 45.8 months, P = 0.036). Endometrioid ovarian cancers with high Thy-1 have poorer PFS, but no difference in OS (upper quartile PFS 34 v. 11 months, P = 0.013; quartile OS not reached, P = 0.69). In vitro, Thy-1 expression is higher in CSCs versus non-CSCs. EOC cells with high Thy-1 expression demonstrate increased proliferation and self-renewal. Thy-1 knockdown in EOC cells decreases proliferative capacity and self-renewal capacity, and knockdown is associated with decreased expression of stem cell transcription factors NANOG and SOX2. RNA in situ hybridization is feasible in ovarian cancer tissue specimens.ConclusionsThy-1 is a marker of ovarian CSCs. Increased expression of Thy-1 in EOC predicts poor prognosis and is associated with increased proliferative and self-renewal capacity. Thy-1 knockdown decreases proliferative and self-renewal capacity, and represents a potential therapeutic target.

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Activation of YAP1 is associated with poor prognosis and response to taxanes in ovarian cancer.

Publications

Activation of YAP1 is associated with poor prognosis and response to taxanes in ovarian cancer.

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