Fos-related antigen 1 modulates malignant features of glioma cells

Mol Cancer Res. 2005 Apr;3(4):237-49. doi: 10.1158/1541-7786.MCR-05-0004.


Malignant gliomas, and high-grade gliomas (HGG) in particular, are nonmetastasizing but locally infiltrating, hypervascularized brain tumors of poor prognosis. We found previously that a c-fos-inducible vascular endothelial growth factor D is ubiquitously up-regulated in HGG grade IV, glioblastoma multiforme, and that glioblastoma multiforme overexpress Fos-related antigen 1 (Fra-1) rather than the c-Fos. We have thus become interested in the role Fra-1 may play in malignant glioma progression/maintenance, because Fra-1 has the capacity to modulate transcription of a variety of target genes. In this work, we have analyzed the biological effects of ectopic Fra-1 expression or Fra-1 knockdown in malignant glioma cells. Ectopic Fra-1 induced prominent phenotypic changes in all three malignant glioma cell lines examined: H4, U-87 MG, and A-172 MG. These changes were reflected in cells becoming more elongated with larger number of cellular processes. Furthermore, Fra-1 transgene caused H4 cells, which do not form tumor xenografts, to regain tumorigenic capacity. The genotype of these cells changed too, because 50 of 1,056 genes examined became either up-regulated or down-regulated. Conversely, Fra-1 knockdown altered prominently the morphology, anchorage-independent growth, tumorigenic potential, and Fra-1 effector expression, such as vascular endothelial growth factor D, in HGG cells. For example, cells transfected with antisense fra-1 showed shorter cellular processes than the control cells that did not grow in agar, and their tumorigenic potential was significantly diminished. Thus, Fra-1 may likely play an important role in the maintenance/progression of malignant gliomas and potentially represents a new target for therapeutic interventions.

MeSH terms

  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology*
  • Cell Adhesion / physiology
  • Cell Division / physiology
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Genotype
  • Glioma / metabolism
  • Glioma / pathology*
  • Humans
  • Neoplasm Invasiveness
  • Phenotype
  • Proto-Oncogene Proteins c-fos / genetics*
  • Proto-Oncogene Proteins c-fos / metabolism*
  • RNA, Messenger / metabolism
  • Transcription Factor AP-1 / metabolism
  • Transcriptional Activation
  • Transgenes


  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Transcription Factor AP-1
  • fos-related antigen 1