miR-183 in prostate cancer cells positively regulates synthesis and serum levels of PSA

Background: Factors affecting serum PSA levels in men are clinically important, but, apart from effects mediated through the androgen receptor, poorly understood. Objective: To investigate whether microRNA (miRNA) affects synthesis and serum levels of PSA. Design, setting and participants: Reporter assays with PSA and KLK2 3’UTRs to confirm posttranscriptional regulation was followed by high-throughput screening of 1129 miRNAs effect on PSA levels, using reverse phase protein arrays (RPPA), to identify individual regulatory miRNAs. The candidate miRNAs were investigated further in vitro by western blot, immunoflourometric, activity assays, qRT-PCR, reporter assays and growth assays, and prostate levels of miR-183 was compared to PSA transcript and serum PSA levels in prostate cancer cohorts. Outcome measurements and statistical analysis: RankProd was used to evaluate the RPPA and Student’s t test was used for the in vitro experiments. In the patient material, Spearman’s and Cuzick’s tests were used and overall survival analysed by the Kaplan-Meier and Log-Rank analysis. Results and limitations: Gain-of-function screenings identified 32 miRNA increasing PSA levels. One of these, miR-183, was found to directly bind the 3’UTR of PSA and increase both protein and mRNA levels, and 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 WHO grade and clinical progression. Conclusions: The synthesis and serum levels of PSA are directly affected by mir-183 and may be a factor to take into consideration when PSA values are evaluated in clinical settings. Patient summary: These findings give novel insight into the regulation of PSA and may eventually affect the clinical decision making of prostate cancer.