The miR-143/-145 cluster regulates plasminogen activator inhibitor-1 in bladder cancer |
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Authors: | Villadsen S B Bramsen J B Ostenfeld M S Wiklund E D Fristrup N Gao S Hansen T B Jensen T I Borre M Ørntoft T F Dyrskjøt L Kjems J |
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Institution: | 1.Department of Molecular Biology, Aarhus University, C.F. Møllers Allé Build, 1130, Aarhus C 8000, Denmark;2.Department of Molecular Medicine, Aarhus University Hospital, Brendstrupgårdsvej 100, Aarhus N 8200, Denmark;3.Department of Urology, Aarhus University Hospital, Brendstrupgårdsvej 100, Aarhus N 8200, Denmark |
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Abstract: | Background: Upregulation of the proto-oncogene plasminogen activator inhibitor-1 (PAI-1) is a common hallmark of various solid tumours, but the mechanisms controlling its expression are not fully understood.Methods: We investigate microRNAs (miRNAs) regulating PAI-1 in a panel of normal bladder urothelial biopsies, superficial Ta bladder tumours and invasive T1–T4 tumours using expression microarrays and qRT–PCR. The prognostic implications of PAI-1 deregulation are established by tissue microarray staining of non-muscle-invasive bladder tumours. MicroRNA repression of PAI-1 is assayed by ectopic miRNA expression, argonaute immunoprecipitation and luciferase assays.Results: We found that the miR-143/-145 cluster is downregulated in all stages of bladder cancer and inversely correlated with PAI-1 expression. Mature miR-143 and miR-145 are coordinately expressed, and both directly target the PAI-1 3′UTR, leading to reduced PAI-1 mRNA and protein levels. Furthermore, we show that PAI-1 and miR-145 levels may serve as useful prognostic markers for non-muscle-invasive bladder tumours for which accurate progressive outcome is currently difficult to predict.Conclusion: This report provides the first evidence for direct miRNA regulation of PAI-1 in bladder cancer. We also demonstrate mRNA co-targeting by a cluster of non-family miRNAs, and suggest miR-145 and PAI-1 as clinically relevant biomarkers in bladder cancer. |
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Keywords: | bladder cancer PAI-1 microRNA miR-143 miR-145 |
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