Terrile, M., Bryan, K., Vaughan, L., Hallsworth, A., Webber, H., Chesler, L., Stallings, R. L. (2011) miRNA Expression Profiling of the Murine TH-MYCN Neuroblastoma Model Reveals Similarities with Human Tumors and Identifies Novel Candidate MiRNAs. PLOS ONE, 6 (12). ISSN 1932-6203

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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. Principal Findings: 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. Significance: 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.

Item Type:	Article
Authors (ICR Faculty only):	Chesler, Louis
All Authors:	Terrile, M., Bryan, K., Vaughan, L., Hallsworth, A., Webber, H., Chesler, L., Stallings, R. L.
Additional Information:	ISI Document Delivery No.: 863NO Times Cited: 0 Cited Reference Count: 51 Terrile, Marta Bryan, Kenneth Vaughan, Lynsey Hallsworth, Albert Webber, Hannah Chesler, Louis Stallings, Raymond L. Science Foundation Ireland[07/IN.1/B1776]; Children's Medical and Research Foundation; Neuroblastoma Society[NES003X] This work was supported in part by Science Foundation Ireland (07/IN.1/B1776), Children's Medical and Research Foundation, and The Neuroblastoma Society, grant NES003X. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. Public library science San francisco
Uncontrolled Keywords:	cell differentiation chromosomal imbalances transcriptional target malignant progression microrna expression suppressor network transgenic model down-regulation retinoic acid p53
Research teams:	ICR divisions > Clinical Studies > Paediatric Solid Tumour Biology and Therapeutics ICR divisions > Cancer Therapeutics > Paediatric Solid Tumour Biology and Therapeutics ICR divisions > Molecular Pathology > Paediatric Solid Tumour Biology and Therapeutics
Depositing User:	Users 11 not found.
Date Deposited:	20 Feb 2012 10:50
Last Modified:	11 Mar 2014 15:55
URI:	http://publications.icr.ac.uk/id/eprint/11394

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