title: miRNA expression profiling of the murine TH-MYCN neuroblastoma model reveals similarities with human tumors and identifies novel candidate miRNAs.
abstract: BACKGROUND
  MicroRNAs are small molecules which regulate gene expression post-transcriptionally and aberrant expression of several miRNAs is associated with neuroblastoma, a childhood cancer arising from precursor cells of the sympathetic nervous system. Amplification of the MYCN transcription factor characterizes the most clinically aggressive subtype of this disease, and although alteration of p53 signaling is not commonly found in primary tumors, deregulation of proteins involved in this pathway frequently arise in recurrent disease after pharmacological treatment. TH-MYCN is a well-characterized transgenic model of MYCN-driven neuroblastoma which recapitulates many clinicopathologic features of the human disease. Here, we evaluate the dysregulation of miRNAs in tumors from TH-MYCN mice that are either wild-type (TH-MYCN) or deficient (TH-MYCN/p53ER(TAM)) for the p53 tumor suppressor gene.
  
  
  RESULTS
  We analyzed the expression of 591 miRNAs in control (adrenal) and neuroblastoma tumor tissues derived from either TH-MYCN or TH-MYCN/p53ER(TAM) mice, respectively wild-type or deficient in p53. Comparing miRNA expression in tumor and control samples, we identified 159 differentially expressed miRNAs. Using data previously obtained from human neuroblastoma samples, we performed a comparison of miRNA expression between murine and human tumors to assess the concordance between murine and human expression data. Notably, the miR-17-5p-92 oncogenic polycistronic cluster, which is over-expressed in human MYCN amplified tumors, was over-expressed in mouse tumors. Moreover, analyzing miRNAs expression in a mouse model (TH-MYCN/p53ER(TAM)) possessing a transgenic p53 allele that drives the expression of an inactive protein, we identified miR-125b-3p and miR-676 as directly or indirectly regulated by the level of functional p53.
  
  
  CONCLUSIONS
  Our study represents the first miRNA profiling of an important mouse model of neuroblastoma. Similarities and differences in miRNAs expression between human and murine neuroblastoma were identified, providing important insight into the efficacy of this mouse model for assessing miRNA involvement in neuroblastoma and their potential effectiveness as therapeutic targets.
authors.affiliation: Department of Cancer Genetics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Marta
authors.initials: M
authors.lastname: Terrile
authors.forename: Kenneth
authors.initials: K
authors.lastname: Bryan
authors.forename: Lynsey
authors.initials: L
authors.lastname: Vaughan
authors.forename: Albert
authors.initials: A
authors.lastname: Hallsworth
authors.forename: Hannah
authors.initials: H
authors.lastname: Webber
authors.forename: Louis
authors.initials: L
authors.lastname: Chesler
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Stallings
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C571825:MYCN protein, mouse; D035683:MicroRNAs; D000071447:N-Myc Proto-Oncogene Protein; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53