Abstract 5906: NUAK2 is highly overexpressed in ovarian cancer and the overexpression of its nuclear form correlates with tumor aggressiveness

Abstract

<p>NUAK2, also known as sucrose non-fermenting (SNF1)-like AMPK-related kinase (SNARK), belongs to the AMPK serine/threonine kinase family. While little is known about the exact biological functions of NUAK2, this kinase has been reported to be overexpressed in multiple cancer types, forming a part of the 1q32 amplicon common in human cancer. When we analysed its expression in the ovarian datasets of The Cancer Genome Atlas and Genotype-Tissue Expression involving 418 ovarian carcinomas and 88 normal ovarian tissues, the level of NUAK2 mRNA was approximately 64-fold elevated in ovarian cancer relative to normal ovaries (p<0.0001). Herein, we aim to gain insights into the potential relevance of NUAK2 overexpression in ovarian cancer and to characterize the functional roles of NUAK2 involved in ovarian carcinogenesis.</p><p>We performed an immunohistochemical study of NUAK2 in a clinical archive of ovarian tumor tissues, a cohort consisting of 10 cases of benign ovarian tumors, 9 cases of borderline ovarian tumors, and 88 cases of ovarian carcinomas. Representative ovarian tumor regions of each individual case were analysed using ImageScope, and a histoscore was then generated as a product of staining percentage and intensity. Histoscores together with clinicopathological data of each patient were subjected to statistical analysis by SPSS and GraphPad. In concordance with the public database, the level of NUAK2 protein was significantly higher in ovarian cancer tissues compared to benign and borderline ovarian tissues (p<0.0001). Histoscores of nuclear NUAK2 in particular were positively correlated with high FIGO grade (p=0.0048); a trend of association, though not statistically significant, between nuclear NUAK2 overexpression and poor overall survival rates also existed (p=0.0602). Since NUAK2 is highly overexpressed in ovarian cancer, in vitro functional assays were then performed to determine whether it plays the roles in regulating proliferation and migration of ovarian cancer cells. Cell proliferation was not impeded upon siRNA-mediated knockdown of NUAK2 in OVCAR3 as determined by MTT assay, and Transwell assay showed that ectopic overexpression of NUAK2 in SKOV3 cells had no prominent effect on migration. Together, this study confirmed NUAK2 overexpression in ovarian cancer consistent with the public databases and also postulates the prognostic value of its nuclear form in predicting tumor aggressiveness and disease outcomes of ovarian cancer patients. However, our current study of proliferation and migration in ovarian cancer cells could not address the functional significance of NUAK2 as reflected in its overexpression pattern. It would be important for our future work to identify particular ovarian cancer genotypes that correlate with NUAK2 expression and thereby functionally drive cooperative tumorigenesis together with NUAK2.</p>