Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status

Lab Invest. 2010 Feb;90(2):144-55. doi: 10.1038/labinvest.2009.126. Epub 2010 Jan 4.

Abstract

MicroRNAs (miRNAs) are a class of endogenous small noncoding RNAs that regulate gene expression after transcription. Aberrant expression of miRNAs has been shown to be involved in tumorigenesis. We showed that miR-21 was one of the most frequently overexpressed miRNA in human glioblastoma (GBM) cell lines. To explore whether miR-21 can serve as a therapeutic target for glioblastoma, we downregulated miR-21 with a specific antisense oligonucleotide and found that apoptosis was induced and cell-cycle progression was inhibited in vitro in U251 (PTEN mutant) and LN229 (PTEN wild-type) GBM cells; xenograft tumors from antisense-treated U251 cells were suppressed in vivo. Antisense-miR-21-treated cells showed a decreased expression of EGFR, activated Akt, cyclin D, and Bcl-2. Although miR-21 is known to regulate PTEN and downregulation of miR-21 led to increased PTEN expression both endogenously and in a reporter gene assay, the GBM suppressor effect of antisense-miR-21 is most likely independent of PTEN regulation because U251 has mutant PTEN. Microarray analysis showed that the knockdown of miR-21 significantly altered expression of 169 genes involved in nine cell-cycle and signaling pathways. Taken together, our studies provide evidence that miR-21 may serve as a novel therapeutic target for malignant gliomas independent of PTEN status.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Line, Tumor
  • Cyclin D / metabolism
  • Down-Regulation*
  • ErbB Receptors / metabolism*
  • Female
  • Gene Expression Profiling
  • Glioblastoma / metabolism*
  • Humans
  • Metabolic Networks and Pathways
  • Mice
  • Mice, Nude
  • MicroRNAs / metabolism*
  • Neoplasm Transplantation
  • Oligonucleotide Array Sequence Analysis
  • Oligonucleotides, Antisense
  • PTEN Phosphohydrolase / physiology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Signal Transduction
  • Transplantation, Heterologous

Substances

  • Cyclin D
  • MIRN21 microRNA, human
  • MicroRNAs
  • Oligonucleotides, Antisense
  • Proto-Oncogene Proteins c-bcl-2
  • ErbB Receptors
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human