Post-transcriptional regulation of MRE11 expression in muscle-invasive bladder tumours
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Rebecca M. Martin1, Martin Kerr1, Mark T.W. Teo2, Sarah J. Jevons1, Marianne Koritzinsky3, Bradly G. Wouters3, Selina Bhattarai4, Anne E. Kiltie1
1 Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, UK
2 Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, Leeds, UK
3 Princess Margaret Cancer Centre, University Health Network, Toronto, Canada and Department of Radiation Oncology, University of Toronto, Toronto, Canada
4 Department of Histopathology and Molecular Pathology, St James’s University Hospital, Leeds, UK
Anne E Kiltie, email:
Key words: MRE11, bladder cancer, post-transcriptional regulation, microRNA, miR-153, protein stability
Received: November 25, 2013 Accepted: January 14, 2014 Published: January 14, 2014
Predictive assays are needed to help optimise treatment in muscle-invasive bladder cancer, where patients can be treated by either cystectomy or radical radiotherapy. Our finding that low tumour MRE11 expression is predictive of poor response to radiotherapy but not cystectomy was recently independently validated. Here we investigated further the mechanism underlying low MRE11 expression seen in poorly-responding patients. MRE11 RNA and protein levels were measured in 88 bladder tumour patient samples, by real-time PCR and immunohistochemistry respectively, and a panel of eight bladder cancer cell lines was screened for MRE11, RAD50 and NBS1 mRNA and protein expression. There was no correlation between bladder tumour MRE11 protein and RNA scores (Spearman’s rho 0.064, p=0.65), suggesting MRE11 is controlled post-transcriptionally, a pattern confirmed in eight bladder cancer cell lines. In contrast, NBS1 and RAD50 mRNA and protein levels were correlated (p=0.01 and p=0.03, respectively), suggesting primary regulation at the level of transcription. MRE11 protein levels were correlated with NBS1 and RAD50 mRNA and protein levels, implicating MRN complex formation as an important determinant of MRE11 expression, driven by RAD50 and NBS1 expression. Our findings of the post-transcriptional nature of the control of MRE11 imply that any predictive assays used in patients need to be performed at the protein level rather than the mRNA level.
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