Abstract
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. 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. 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 < 0.045). RNAi-mediated silencing of NUAK1 expression attenuated migration of OV90 and E3 HGSOC cells in vitro, but did not modulate sensitivity to cisplatin or paclitaxel. Elevated NUAK1 was associated with poor survival as well as advanced stage, residual disease after cytoreductive surgery and mesenchymal molecular subtype. NUAK1 impacted migration, but not chemosensitivity, in vitro. Additional studies are needed to further develop the concept of NUAK1 as a clinically deployable biomarker and therapeutic target in HGSOC.
Highlights
High-grade serous ovarian cancer (HGSOC) will comprise approximately 70% of the estimated 21,290 new diagnoses of ovarian malignancy in the US in 2016 [1, 2]
NUAK1 transcript expression was assessed in a cohort of 1,262 patients assembled from seven publicly available, ovarian cancer Affymetrix microarray data sets downloaded from the curatedOvarianData database [14] and an independent cohort of 174 HGSOC patients with Agilent gene expression data [8] (Table 1)
Using publicly available transcript expression data from 1,262 ovarian cancer patients, we show that elevated NUAK1 is associated with decreased overall survival (OS) and progression-free survival (PFS)
Summary
High-grade serous ovarian cancer (HGSOC) will comprise approximately 70% of the estimated 21,290 new diagnoses of ovarian malignancy in the US in 2016 [1, 2]. Though HGSOC is an ominous diagnosis, considerable variation exists between patients in terms of the time from diagnosis to disease progression and cancer death. Common features of shorter progression-free survival (PFS) and overall survival (OS) in HGSOC patients include older age, advanced stage and dissemination of disease into the upper abdominal cavity at diagnosis, and presence of residual tumor following cytoreductive surgery [1, 3, 4]. 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
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