title: Post-transcriptional regulation of MRE11 expression in muscle-invasive bladder tumours.
abstract: 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.
authors.affiliation: Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, UK.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Martin
authors.forename: Martin
authors.initials: M
authors.lastname: Kerr
authors.forename: Mark T W
authors.initials: MT
authors.lastname: Teo
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Jevons
authors.forename: Marianne
authors.initials: M
authors.lastname: Koritzinsky
authors.forename: Bradly G
authors.initials: BG
authors.lastname: Wouters
authors.forename: Selina
authors.initials: S
authors.lastname: Bhattarai
authors.forename: Anne E
authors.initials: AE
authors.lastname: Kiltie
mesh_terms: D020413:3' Untranslated Regions; D017766:Acid Anhydride Hydrolases; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D045643:DNA Repair Enzymes / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D000076228:MRE11 Homologue Protein; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery*
chemical_list: D020413:3' Untranslated Regions; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C556500:MIRN153 microRNA, human; C121766:MRE11 protein, human; D035683:MicroRNAs; C112156:NBN protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes