miR-34a Functions as a Tumor Suppressor Modulating EGFR in Glioblastoma Multiforme

Oncogene. 2013 Feb 28;32(9):1155-63. doi: 10.1038/onc.2012.132. Epub 2012 May 14.

Abstract

Chromosome 1p36.23 is frequently deleted in glioblastoma multiforme (GBM). miR-34a localizes in this region. Our experiments found that miR-34a was often deleted and epidermal growth factor receptor (EGFR) was frequently amplified in genomic DNA of 55 GBMs using single-nucleotide polymorphism DNA microarray. Notably, we found that the mean survival time was significantly shortened for patients whose GBMs had both EGFR amplification and miR-34a deletion. Expression of miR-34a was significantly lower in GBM samples compared with normal brain tissue. Forced expression of miR-34a in GBM cells decreased their ability to migrate and profoundly decreased their levels of cyclin-A1, -B1, -D1, and -D3, as well as cyclin-dependent kinase and increased expression of cyclin kinase inhibitor proteins (p21, p27). Also, human GBM cells (U251) stable overexpressing mir-34a formed smaller tumors when growing as xenografts in immunodeficient mice compared with wild-type U251 GBM cells. Furthermore, the protein expression of EGFR decreased in the cells with forced overexpression of miR-34a. Additional studies showed that mir-34a targeted Yin Yang-1 (YY1) and YY1 is a transcription factor that can stimulate the expression of EGFR. Thus, our data suggest that miR-34a acts as a tumor suppressor by inhibiting growth of GBM cells in vitro and in vivo associated with moderating the expression of cell-cycle proteins and EGFR. Moreover, we discovered for the first time that both deletion of miR-34a and amplification of EGFR were associated with significantly decreased overall survival of GBM patients.

Publication types

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

MeSH terms

  • Animals
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / metabolism
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • ErbB Receptors / genetics*
  • ErbB Receptors / metabolism
  • Gene Amplification
  • Gene Deletion
  • Gene Expression Regulation, Neoplastic*
  • Genes, Tumor Suppressor
  • Glioblastoma / genetics*
  • Glioblastoma / mortality
  • Glioblastoma / pathology
  • Humans
  • Mice
  • Mice, Nude
  • MicroRNAs / physiology*
  • Transplantation, Heterologous
  • YY1 Transcription Factor / metabolism

Substances

  • Cell Cycle Proteins
  • MIRN34 microRNA, human
  • MicroRNAs
  • YY1 Transcription Factor
  • YY1 protein, human
  • ErbB Receptors