Splice variant transcripts of the anterior gradient 2 gene as a marker of prostate cancer

Abstract

// Antje Neeb 1,* , Simon Hefele 2,* , Stefanie Bormann 1,8 , Walther Parson 3,4 , Fabian Adams 5 , Philipp Wolf 5 , Arkadiusz Miernik 5 , Martin Schoenthaler 5 , Malte Kroenig 5 , Konrad Wilhelm 5 , Wolfgang Schultze-Seemann 5 , Sigrun Nestel 6 , Georg Schaefer 7 , Huajie Bu 7 , Helmut Klocker 7 , Irina Nazarenko 2,* and Andrew C. B. Cato 1,* 1 Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, Eggenstein-Leopoldshafen, Germany 2 Department of Environmental Health Sciences and Hospital Infection Control, Medical Center-University of Freiburg, Freiburg, Germany 3 Institute of Legal Medicine, Innsbruck Medical University, Innsbruck, Austria 4 Penn State Eberly College of Science, University Park, PA, USA 5 Department of Urology, Medical Center-University of Freiburg, Freiburg, Germany 6 Institute of Anatomy and Cell Biology, University of Freiburg, Freiburg, Germany 7 Department of Urology, Division of Experimental Urology, Innsbruck Medical University, Innsbruck, Austria 8 Heinrich Heine University, Institute of Toxicology, Düsseldorf, Germany * These authors contributed equally to this work Correspondence: Antje Neeb, email: // Irina Nazarenko, email: // Keywords : Anterior gradient 2 gene, Exosomes, Prostate cancer diagnosis, Urinary biomarkers, Splice variants Received : June 16, 2014 Accepted : August 18, 2014 Published : August 19, 2014 Abstract Anterior gradient 2 (AGR2) is a gene predominantly expressed in mucus-secreting tissues or in endocrine cells. Its expression is drastically increased in tumors including prostate cancer. Here we investigated whether AGR2 transcript levels can be used as a biomarker to detect prostate cancer (PCa). Using a PCR-based approach, we could show that in addition to the wild-type (AGRwt long and short) transcripts, five other AGR2 splice variants (SV) (referred to as AGR2 SV-C, -E, -F, -G and -H) were present in cancer cell lines. In tissue biopsies, SV-H and AGR2wt (short) distinguished between benign and PCa (p ≤ 0.05 n = 32). In urine exosomes, AGR2 SV-G and SV-H outperformed serum PSA. Receiver operating characteristic (ROC) curves showed the highest discriminatory power of SV-G and SV-H in predicting PCa. AGR2 SV-G and SV-H are potential diagnostic biomarkers for the non-invasive detection of PCa using urine exosomes.