OncoTargets and Therapy (Jul 2017)
Nuclear DDX3 expression predicts poor outcome in colorectal and breast cancer
Abstract
Marise R Heerma van Voss,1,2 Farhad Vesuna,2 Guus M Bol,1,2 Jan Meeldijk,1,3 Ana Raman,4 G Johan Offerhaus,1 Horst Buerger,5 Arvind H Patel,6 Elsken van der Wall,7,8 Paul J van Diest,1,8 Venu Raman1,2,8 1Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands; 2Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 3Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands; 4Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 5Institute of Pathology, Paderborn, Germany; 6Centre for Virus Research, MRC-University of Glasgow, Glasgow, UK; 7Cancer Center, University Medical Center Utrecht, Utrecht, the Netherlands; 8Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Purpose: DEAD box protein 3 (DDX3) is an RNA helicase with oncogenic properties that shuttles between the cytoplasm and nucleus. The majority of DDX3 is found in the cytoplasm, but a subset of tumors has distinct nuclear DDX3 localization of yet unknown biological significance. This study aimed to evaluate the significance of and mechanisms behind nuclear DDX3 expression in colorectal and breast cancer.Methods: Expression of nuclear DDX3 and the nuclear exporter chromosome region maintenance 1 (CRM1) was evaluated by immunohistochemistry in 304 colorectal and 292 breast cancer patient samples. Correlations between the subcellular localization of DDX3 and CRM1 and the difference in overall survival between patients with and without nuclear DDX3 were studied. In addition, DDX3 mutants were created for in vitro evaluation of the mechanism behind nuclear retention of DDX3.Results: DDX3 was present in the nucleus of 35% of colorectal and 48% of breast cancer patient samples and was particularly strong in the nucleolus. Nuclear DDX3 correlated with worse overall survival in both colorectal (hazard ratio [HR] 2.34, P<0.001) and breast cancer (HR 2.39, P=0.004) patients. Colorectal cancers with nuclear DDX3 expression more often had cytoplasmic expression of the nuclear exporter CRM1 (relative risk 1.67, P=0.04). In vitro analysis of DDX3 deletion mutants demonstrated that CRM1-mediated export was most dependent on the N-terminal nuclear export signal.Conclusion: Overall, we conclude that nuclear DDX3 is partially CRM1-mediated and predicts worse survival in colorectal and breast cancer patients, putting it forward as a target for therapeutic intervention with DDX3 inhibitors under development in these cancer types. Keywords: RNA helicase, DDX3X, nuclear export, CRM1
