title: miRNAs associated with chemo-sensitivity in cell lines and in advanced bladder cancer.
abstract: BACKGROUND
  MicroRNA is a naturally occurring class of non-coding RNA molecules that mediate posttranscriptional gene regulation and are strongly implicated in cellular processes such as cell proliferation, carcinogenesis, cell survival and apoptosis. Consequently there is increasing focus on miRNA expression as prognostic factors for outcome and chemotherapy response. Only approximately 50% of patients with bladder cancer respond to chemotherapy. Therefore, predictive markers, such as miRNAs, that can identify subgroups of patients who will benefit from chemotherapy will have great value for treatment guidance.
  
  
  METHODS
  We profiled the expression of 671 miRNAs in formalin fixed paraffin embedded tumors from patients with advanced bladder cancer treated with cisplatin based chemotherapy. We delineated differentially expressed miRNAs in tumors from patients with complete response vs. patients with progressive disease and in tumors form patients with short and long overall survival time. Furthermore, we studied the effect of up- and down regulation of key miRNAs on the cisplatin sensitivity in eight bladder cancer cell lines with different sensitivities to cisplatin.
  
  
  RESULTS
  miRNA expression profiling identified 15 miRNAs that correlated with response to chemotherapy and 5 miRNAs that correlated with survival time. Three miRNAs were associated with both response and survival (886-3p, 923, 944). By changing the cellular level of the response-identified miRNAs in eight bladder cell lines with different cisplatin sensitivity we found that down-regulation of miR-27a, miR296-5p and miR-642 generally reduced the cell viability, whereas up-regulation of miR-138 and miR-886-3p reduced the viability of more than half of the cell lines. Decreasing miR-138 increased the cisplatin sensitivity in half of the cell lines and increasing miR-27a and miR-642 generally increased cisplatin sensitivity.
  
  
  CONCLUSIONS
  MiRNAs seem to be involved in cisplatin based chemo response and may form a new target for therapy and serve as biomarkers for treatment response.
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark. iver.nordentoft@ki.au.dk
authors.forename: Iver
authors.initials: I
authors.lastname: Nordentoft
authors.forename: Karin
authors.initials: K
authors.lastname: Birkenkamp-Demtroder
authors.forename: Mads
authors.initials: M
authors.lastname: Agerbæk
authors.forename: Dan
authors.initials: D
authors.lastname: Theodorescu
authors.forename: Marie Stampe
authors.initials: MS
authors.lastname: Ostenfeld
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Michael
authors.initials: M
authors.lastname: Borre
authors.forename: Torben F
authors.initials: TF
authors.lastname: Ørntoft
authors.forename: Lars
authors.initials: L
authors.lastname: Dyrskjøt
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009367:Neoplasm Staging; D012015:Reference Standards; D015203:Reproducibility of Results; D016019:Survival Analysis; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D035683:MicroRNAs; D002945:Cisplatin