Journal
BRITISH JOURNAL OF CANCER
Volume 106, Issue 2, Pages 366-374Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2011.520
Keywords
bladder cancer; PAI-1; microRNA; miR-143; miR-145
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Funding
- SIROCCO EU consortium
- Fabrikant Vilhelm Pedersens og Hustrus Mindelegat
- Danish Council for Independent Research
- Lundbeck Foundation [R83-2011-8232] Funding Source: researchfish
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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 30UTR, 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. British Journal of Cancer (2012) 106, 366-374. doi:10.1038/bjc.2011.520 www.bjcancer.com Published online 22 November 2011 (C) 2012 Cancer Research UK
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