Larne O., Östling P., Haflidadóttir B.S., Hagman Z., Aakula A., Kohonen P., Kallioniemi O., Edsjö A., Bjartell A., Lilja H., Lundwall A., Ceder Y.
European Urology 2015 68:4 (581-588)
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