Nucleolar localization of the RNA helicase DDX21 is associated with decreased survival in advanced-stage endometrioid endometrial cancer

Abstract

<h3>Objectives:</h3> DDX21 is a RNA helicase that promotes rDNA transcription when ADP-ribosylated, leading to cell growth via ribosome biogenesis and protein translation. Poly-ADP-ribose-1 (PARP-1) catalytic activity in the cell nucleolus can lead to ADP-ribosylation of DDX21. Recent evidence suggests an association of elevated PARP-1 and DDX21 nucleolar localization with outcomes in breast cancer, identifying an alternative pathway for PARP inhibition that is not associated with DNA repair defects. The aim of this study is to investigate if there is an association between DDX21 nucleolar localization or PARP-1 expression and clinical outcomes. <h3>Methods:</h3> Thirty-nine patient samples with stage IIIA-IVB endometrioid endometrial cancer who received upfront cancer staging were collected. Demographics, clinical, pathologic, and survival outcome data were recorded. Immunohistochemical (IHC) analysis for DDX21 and PARP-1 was performed and analyzed by a gynecologic pathologist. Samples were analyzed for PARP-1 expression and localization of DDX21 staining in the nucleolus, pan-nucleus, or cytosol. The same analysis was performed on a commercially available tissue microarray for comparisons in demographic data. Associations were investigated using t-tests, one-way ANOVA and Kaplan-Meier survival analysis. <h3>Results:</h3> DDX21 and PARP-1 expression was not associated with survival in advanced stage endometrioid endometrial cancer patient samples. However, high nucleolar localization of DDX21 was associated with a significantly decreased progression free survival (PFS, p=0.019) and overall survival (OS, p=0.031). Pan-nuclear or cytosolic localization of DDX21 was not associated with differences in survival. DDX21 localization was not correlated with demographics such as grade or stage in our patient samples or commercially available microarray. However, increased DDX21 nucleolar localization was associated with high PARP-1 expression (p<0.0001). <h3>Conclusions:</h3> DDX21 localization to the nucleus is associated with poor prognosis in endometrioid endometrial cancer. This significant difference in prognosis is not due to differences in baseline demographics or clinico-pathologic factors. Increased DDX21 nucleolar localization is also associated with elevated PARP-1 expression. Further laboratory studies are being performed to investigate the effect of ADP-ribosylation and PARP inhibition on DDX21 localization and cell growth in endometrial cancer cells.