MicroRNA profiling in pediatric pilocytic astrocytoma reveals biologically relevant targets, including PBX3, NFIB, and METAP2

Neuro Oncol. 2013 Jan;15(1):69-82. doi: 10.1093/neuonc/nos269. Epub 2012 Nov 15.

Abstract

Pilocytic astrocytoma (PA) is a World Health Organization grade I glioma that occurs most commonly in children and young adults. Specific genetic alterations have been described in PA, but the pathogenesis remains poorly understood. We studied microRNA (miRNA) alterations in a large cohort of patients with PA. A total of 43 PA, including 35 sporadic grade I PA, 4 neurofibromatosis-1 (NF1)-associated PA, and 4 PA with pilomyxoid features, as well as 5 nonneoplastic brain controls were examined. BRAF fusion status was assessed in most cases. RNA was examined using the Agilent Human miRNA Microarray V3 platform. Expression of miRNA subsets was validated using quantitative real-time PCR (qRT-PCR) with Taqman probes. Validation of predicted protein targets was performed on tissue microarrays with the use of immunohistochemistry. We identified a subset of miRNAs that were differentially expressed in pediatric PAs versus normal brain tissue: 13 miRNAs were underexpressed, and 20 miRNAs were overexpressed in tumors. Differences were validated by qRT-PCR in a subset, with mean fold change in tumor versus brain of -17 (miR-124), -15 (miR-129), and 19.8 (miR-21). Searching for predicted protein targets in Targetscan, we identified a number of known and putative oncogenes that were predicted targets of miRNA sets relatively underexpressed in PA. Predicted targets with increased expression at the mRNA and/or protein level in PA included PBX3, METAP2, and NFIB. A unique miRNA profile exists in PA, compared with brain tissue. These miRNAs and their targets may play a role in the pathogenesis of PA.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aminopeptidases / genetics
  • Aminopeptidases / metabolism*
  • Astrocytoma / genetics*
  • Astrocytoma / metabolism
  • Astrocytoma / pathology
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Case-Control Studies
  • Cerebellum / metabolism
  • Cerebellum / pathology
  • Child
  • Child, Preschool
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Glycoproteins / genetics
  • Glycoproteins / metabolism*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Immunoenzyme Techniques
  • Infant
  • Male
  • MicroRNAs / genetics*
  • NFI Transcription Factors / genetics
  • NFI Transcription Factors / metabolism*
  • Neoplasm Grading
  • Oligonucleotide Array Sequence Analysis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tissue Array Analysis
  • Young Adult

Substances

  • Biomarkers, Tumor
  • Glycoproteins
  • Homeodomain Proteins
  • MicroRNAs
  • NFI Transcription Factors
  • NFIB protein, human
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • proto-oncogene protein Pbx3
  • Aminopeptidases
  • METAP2 protein, human