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NUAK1 (ARK5) Is Associated with Poor Prognosis in Ovarian Cancer.

ABSTRACT: BACKGROUND AND OBJECTIVE:Nua kinase 1 (NUAK1) was identified in multigene signatures of survival and suboptimal debulking in high-grade serous ovarian cancer (HGSOC). This study investigates the individual clinical and biologic contributions of NUAK1 in HGSOC patients and cell lines. METHODS:Public transcript expression, clinical, and outcome data were used to interrogate the relationship between NUAK1 and clinicopathologic factors and patient outcomes including progression-free survival (PFS) and molecular subtypes using logistic and Cox modeling. Analysis of NUAK1 transcript expression was performed in primary tumors from 34 HGSOC patients with < or ?2?years PFS. The impact of silencing NUAK1 by RNA interference (RNAi) on the migratory potential and chemosensitivity of SOC cells was assessed in vitro. RESULTS:Elevated NUAK1 transcript expression was associated with worse PFS (hazard ratio?=?1.134), advanced stage (odds ratio, OR?=?1.7), any residual disease (OR?=?1.58), and mesenchymal disease subtype (OR?=?7.79?±?5.89). Elevated NUAK1 transcript expression was observed in HGSOC patients with < vs. ?2?years PFS (p?

SUBMITTER: Phippen NT

PROVIDER: S-EPMC5081368 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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NUAK1 (ARK5) Is Associated with Poor Prognosis in Ovarian Cancer.

Phippen Neil T NT Bateman Nicholas W NW Wang Guisong G Conrads Kelly A KA Ao Wei W Teng Pang-Ning PN Litzi Tracy A TA Oliver Julie J Maxwell G Larry GL Hamilton Chad A CA Darcy Kathleen M KM Conrads Thomas P TP

Frontiers in oncology 20161027

<h4>Background and objective</h4>Nua kinase 1 (NUAK1) was identified in multigene signatures of survival and suboptimal debulking in high-grade serous ovarian cancer (HGSOC). This study investigates the individual clinical and biologic contributions of NUAK1 in HGSOC patients and cell lines.<h4>Methods</h4>Public transcript expression, clinical, and outcome data were used to interrogate the relationship between NUAK1 and clinicopathologic factors and patient outcomes including progression-free s ...[more]

PMID: 27833898

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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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NUAK1 (ARK5) Is Associated with Poor Prognosis in Ovarian Cancer.

Publications

NUAK1 (ARK5) Is Associated with Poor Prognosis in Ovarian Cancer.

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