Micro-RNA-128 (miRNA-128) down-regulation in glioblastoma targets ARP5 (ANGPTL6), Bmi-1 and E2F-3a, key regulators of brain cell proliferation

J Neurooncol. 2010 Jul;98(3):297-304. doi: 10.1007/s11060-009-0077-0. Epub 2009 Nov 26.

Abstract

High density micro-RNA (miRNA) arrays, fluorescent-reporter miRNA assay and Northern miRNA dot-blot analysis show that a brain-enriched miRNA-128 is significantly down-regulated in glioblastoma multiforme (GBM) and in GBM cell lines when compared to age-matched controls. The down-regulation of miRNA-128 was found to inversely correlate with WHO tumor grade. Three bioinformatics-verified miRNA-128 targets, angiopoietin-related growth factor protein 5 (ARP5; ANGPTL6), a transcription suppressor that promotes stem cell renewal and inhibits the expression of known tumor suppressor genes involved in senescence and differentiation, Bmi-1, and a transcription factor critical for the control of cell-cycle progression, E2F-3a, were found to be up-regulated. Addition of exogenous miRNA-128 to CRL-1690 and CRL-2610 GBM cell lines (a) restored 'homeostatic' ARP5 (ANGPTL6), Bmi-1 and E2F-3a expression, and (b) significantly decreased the proliferation of CRL-1690 and CRL-2610 cell lines. Our data suggests that down-regulation of miRNA-128 may contribute to glioma and GBM, in part, by coordinately up-regulating ARP5 (ANGPTL6), Bmi-1 and E2F-3a, resulting in the proliferation of undifferentiated GBM cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Angiopoietin-like Proteins
  • Angiopoietins / genetics
  • Angiopoietins / metabolism*
  • Brain / pathology*
  • Brain Neoplasms / pathology*
  • Cell Proliferation* / drug effects
  • Computational Biology / methods
  • Down-Regulation / drug effects
  • Down-Regulation / physiology*
  • E2F3 Transcription Factor / genetics
  • E2F3 Transcription Factor / metabolism*
  • Female
  • Glioblastoma / pathology*
  • Humans
  • Male
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • MicroRNAs / pharmacology
  • Middle Aged
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Polycomb Repressive Complex 1
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Messenger / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Transfection / methods

Substances

  • ANGPTL6 protein, human
  • Angiopoietin-like Proteins
  • Angiopoietins
  • BMI1 protein, human
  • E2F3 Transcription Factor
  • MIRN128 microRNA, human
  • MicroRNAs
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Repressor Proteins
  • Polycomb Repressive Complex 1