Soluble chemokine (C-X-C motif) ligand 16 (CXCL16) in urine as a novel biomarker candidate to identify high grade and muscle invasive urothelial carcinomas
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Kerstin Lang1, Nadine Bonberg1, Sibylle Robens1, Thomas Behrens1, Jan Hovanec1, Thomas Deix2, Katharina Braun2, Florian Roghmann2, Joachim Noldus2, Volker Harth3, Karl-Heinz Jöckel4, Raimund Erbel5, Yu Chun Tam6, Andrea Tannapfel6, Heiko Udo Käfferlein1,* and Thomas Brüning1,*
1Institute for Prevention and Occupational Medicine of the German Social Accident Insurances, Ruhr-University Bochum (IPA), Bochum, Germany
2Department of Urology, Universitätsklinik Marien Hospital Herne, Ruhr University Bochum, Herne, Germany
3Institute of Occupational and Maritime Medicine, University Clinic Hamburg-Eppendorf, Hamburg, Germany
4Institute for Medical Informatics, Biometry und Epidemiology (IMIBE), University Hospital of Essen, Essen, Germany
5Department of Cardiology, West-German Heart Center Essen, University Hospital of Essen, Essen, Germany
6Institute of Pathology, Georgius Agricola Stiftung Ruhr, Ruhr University Bochum, Bochum, Germany
*Shared senior authorship
Heiko Udo Käfferlein, email: [email protected]
Keywords: urothelial cancer, chemokine CXCL16, biomarker, urine, tumour biology
Received: February 01, 2017 Accepted: August 07, 2017 Published: September 08, 2017
Information on biomarkers of urothelial carcinomas (UC) for clinical decision-making is limited. Here, we newly identified and verified CXCL16 as a promising novel biomarker in urine for high grade and muscle invasive UC in a cross-sectional cohort of 308 UC patients, 126 urological hospital controls, and 50 population controls using antibody arrays and ELISA. Median CXCL16 levels in urine was significantly higher in UC patients (273.2 pg/mg creatinine) compared to hospital (148.1 pg/mg) and population controls (85.1 pg/mg) with a particular preference for high grade (460.8 pg/mg), muscle invasive (535.7 pg/mg) and primary UC (327.8 pg/mg) (all p<0.0001). Group differences were confirmed after adjusting or stratifying for potential clinical and individual characteristics, such as leukocyte counts, haematuria, age, gender, and smoking status. In contrast, CXCL16 showed less discriminating power in low grade (244.3 pg/mg), non-muscle invasive (≤pT1, 251.2 pg/mg) and recurrent UC (203.9 pg/mg). In agreement with its function in immune defence, expression of CXCL16 in tissue samples of primary UC patients (n=53) showed only a weak or no immunoreactivity compared to urological hospital controls (n=32). Expression of CXCR6, the G-protein-coupled receptor of CXCL16, remained unchanged. Our findings suggest that evading the immune defence by shedding cell-surface CXCL16 and its increased elimination in urine is a molecular feature of high grade and muscle invasive UC. Therefore, urinary CXCL16 may serve as a useful, simple and non-invasive tool to identify high-risk UC with increased risk of progression at the molecular level.
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