Olivia Larne1, Päivi Östling2, Benedikta S Haflidadóttir1, Zandra Hagman1, Anna Aakula2, Pekka Kohonen3, Olli Kallioniemi4, Anders Edsjö5, Anders Bjartell6, Hans Lilja7, Åke Lundwall8, Yvonne Ceder9. 1. Department of Laboratory Medicine, Lund, Division of Clinical Chemistry, Lund University, Malmö, Sweden. 2. Current affiliation: Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland; Medical Biotechnology, VTT Technical Research Centre of Finland, and Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland. 3. Medical Biotechnology, VTT Technical Research Centre of Finland, and Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland; Division of Molecular Toxicology, Institute of Environmental Medicine/Institutet för miljömedicin (IMM), Karolinska Institutet, Solna, Sweden. 4. Current affiliation: Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland. 5. Centre for Molecular Pathology, Lund University, Malmö, Sweden; Current affiliation: Sahlgrenska Cancer Centre, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 6. Department of Clinical Medicine, Urology, Division of Urological Cancers, Lund University, Malmö, Sweden. 7. Department of Laboratory Medicine, Lund, Division of Clinical Chemistry, Lund University, Malmö, Sweden; Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK. 8. Department of Laboratory Medicine, Lund, Division of Translational Cancer Research, Lund University, Lund, Sweden. 9. Department of Laboratory Medicine, Lund, Division of Clinical Chemistry, Lund University, Malmö, Sweden; Department of Laboratory Medicine, Lund, Division of Translational Cancer Research, Lund University, Lund, Sweden. Electronic address: Yvonne.Ceder@med.lu.se.
Abstract
BACKGROUND: Factors affecting serum prostate-specific antigen (PSA) levels in men are clinically important, but apart from effects mediated through the androgen receptor, they are poorly understood. OBJECTIVE: To investigate whether microRNA (miRNA) affects the synthesis and serum levels of PSA. DESIGN, SETTING, AND PARTICIPANTS: Reporter assays with PSA and KLK2 3' untranslated regions (UTRs) to confirm posttranscriptional regulation was followed by high-throughput screening of the effect of 1129 miRNAs on PSA levels using reverse phase protein arrays (RPPAs) to identify individual regulatory miRNAs. The candidate miRNAs were investigated further in vitro by Western blot, immunofluorometrics, activity assays, quantitative reverse transcriptase polymerase chain reaction, reporter assays, and growth assays. Prostate levels of miR-183 were compared with PSA transcript and serum PSA levels in prostate cancer cohorts. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: RankProd was used to evaluate the RPPAs, and the Student t test was used for the in vitro experiments. The Spearman and Cuzick tests were used in the patient material, and overall survival was analysed by Kaplan-Meier and log-rank analysis. RESULTS AND LIMITATIONS: Gain-of-function screenings identified 32 miRNAs that increase PSA levels. One of these, miR-183, was found to bind the 3' UTR of PSA directly and increase both protein and messenger RNA levels. Prostatic levels of miR-183 and serum PSA showed correlation in a cohort of 74 men. In addition, miR-183 promotes cellular growth in vitro and correlates to clinical parameters such as World Health Organisation grade and clinical progression. CONCLUSIONS: The synthesis and serum levels of PSA are directly affected by miR-183 and may be a factor to consider when PSA values are evaluated in clinical settings. PATIENT SUMMARY: These findings offer novel insights into the regulation of prostate-specific antigen and may eventually affect clinical decision making in prostate cancer.
BACKGROUND: Factors affecting serum prostate-specific antigen (PSA) levels in men are clinically important, but apart from effects mediated through the androgen receptor, they are poorly understood. OBJECTIVE: To investigate whether microRNA (miRNA) affects the synthesis and serum levels of PSA. DESIGN, SETTING, AND PARTICIPANTS: Reporter assays with PSA and KLK2 3' untranslated regions (UTRs) to confirm posttranscriptional regulation was followed by high-throughput screening of the effect of 1129 miRNAs on PSA levels using reverse phase protein arrays (RPPAs) to identify individual regulatory miRNAs. The candidate miRNAs were investigated further in vitro by Western blot, immunofluorometrics, activity assays, quantitative reverse transcriptase polymerase chain reaction, reporter assays, and growth assays. Prostate levels of miR-183 were compared with PSA transcript and serum PSA levels in prostate cancer cohorts. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: RankProd was used to evaluate the RPPAs, and the Student t test was used for the in vitro experiments. The Spearman and Cuzick tests were used in the patient material, and overall survival was analysed by Kaplan-Meier and log-rank analysis. RESULTS AND LIMITATIONS: Gain-of-function screenings identified 32 miRNAs that increase PSA levels. One of these, miR-183, was found to bind the 3' UTR of PSA directly and increase both protein and messenger RNA levels. Prostatic levels of miR-183 and serum PSA showed correlation in a cohort of 74 men. In addition, miR-183 promotes cellular growth in vitro and correlates to clinical parameters such as World Health Organisation grade and clinical progression. CONCLUSIONS: The synthesis and serum levels of PSA are directly affected by miR-183 and may be a factor to consider when PSA values are evaluated in clinical settings. PATIENT SUMMARY: These findings offer novel insights into the regulation of prostate-specific antigen and may eventually affect clinical decision making in prostate cancer.
Authors: Mohammad Waseem; Mohammad Kaleem Ahmad; Mohammad Serajuddin; Ved Bhaskar; Satya Narain Sankhwar; Abbas Ali Mahdi Journal: Indian J Clin Biochem Date: 2017-12-29
Authors: Binod Kumar; Salar Khaleghzadegan; Brian Mears; Koji Hatano; Tarana A Kudrolli; Wasim H Chowdhury; David B Yeater; Charles M Ewing; Jun Luo; William B Isaacs; Luigi Marchionni; Shawn E Lupold Journal: Oncotarget Date: 2016-11-08