Abstract
Abstract Objectives: Death-associated protein kinase (DAPK) is a cytoskeleton-associated serine/threonine kinase. It functions as a potent inhibitor of cell polarization and migration. DAPK loss has been shown to be associated with advanced tumor stages and unfavorable prognosis in many tumor types. However, the prognostic relevance of DAPK in patients with colorectal cancer is only poorly understood. Thus, we aimed to investigate the impact of DAPK protein expression on clinical outcome in patients with colorectal cancer. Methods: Samples from 220 colorectal cancer patients with a median follow-up of 60 months were analyzed for immunohistochemical DAPK protein expression on tissue microarrays. The effect of endogenous DAPK protein expression on cell migration was analyzed applying the ECIS system (electric cell-substrate impedance sensing) with stable DAPK knockdown (shRNA) and DAPK overexpressing cell lines generated from HCT116 wild type colon cancer cells. Colony formation ability was analyzed using soft agar assay. Results: In Kaplan-Meier-curve analysis DAPK loss was associated with longer survival time (p< 0.001). The 5-year survival rates were 52.3% and 25.6% in patients with DAPK negative tumors and DAPK positive tumors, respectively. 76.1% of DAPK positive tumors showed evidence of tumor budding. After adjusting for TNM stage in multivariate Cox regression analysis, DAPK retained its strong independent prognostic value. Patients with DAPK overexpressing tumors had a 1.9 times increased risk of death from the tumor than those with DAPK negative tumors. DAPK expression in tumor center showed a loss of expression toward the front (p=0.0126). This was in agreement with ECIS migration results indicating higher migration rate for DAPK shRNA cells. DAPK wild type cells showed an increased number of colonies in soft agar assay in comparison to other cell types. Colony formation ability showed time-dependent effects for DAPK overexpression. Conclusion: In contrast to the well-known function of DAPK as a tumor suppressor, our data showed DAPK overexpression to be associated with aggressiveness of tumors and an unfavorable outcome. This interesting and new finding has to be further evaluated. Citation Format: Jelena Ivanovska, Inti Zlobec, Eva Diamantis-Karamitopoulou, Heather Dawson, Viktor Hendrik Koelzer, Abbas Agaimy, Fabian Garreis, William Laqua, Alessandro Lugli, Arndt Hartmann, Regine Schneider-Stock. High DAPK expression is correlated with worse prognosis in colorectal cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3825. doi:10.1158/1538-7445.AM2014-3825
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