The guanine nucleotide exchange factors trio, Ect2, and Vav3 mediate the invasive behavior of glioblastoma

Am J Pathol. 2008 Dec;173(6):1828-38. doi: 10.2353/ajpath.2008.080043. Epub 2008 Nov 13.

Abstract

Malignant gliomas are characterized by their ability to invade normal brain tissue. We have previously shown that the small GTPase Rac1 plays a role in both migration and invasion in gliomas. Here, we aim to identify Rac-activating guanine nucleotide exchange factors (GEFs) that mediate glioblastoma invasiveness. Using a brain tumor expression database, we identified three GEFs, Trio, Ect2, and Vav3, that are expressed at higher levels in glioblastoma versus low-grade glioma. The expression of these GEFs is also associated with poor patient survival. Quantitative real-time polymerase chain reaction and immunohistochemical analyses on an independent set of tumors confirmed that these GEFs are overexpressed in glioblastoma as compared with either nonneoplastic brain or low-grade gliomas. In addition, depletion of Trio, Ect2, and Vav3 by siRNA oligonucleotides suppresses glioblastoma cell migration and invasion. Depletion of either Ect2 or Trio also reduces the rate of cell proliferation. These results suggest that targeting GEFs may present novel strategies for anti-invasive therapy for malignant gliomas.

Publication types

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

MeSH terms

  • Animals
  • Brain / physiology
  • Cell Line, Tumor
  • Cell Movement / physiology
  • Cell Proliferation
  • Databases, Nucleic Acid
  • Gene Expression Profiling
  • Glioblastoma* / pathology
  • Glioblastoma* / physiopathology
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Neoplasm Invasiveness
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-vav / genetics
  • Proto-Oncogene Proteins c-vav / metabolism*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats
  • Rats, Wistar
  • Reproducibility of Results
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism

Substances

  • ECT2 protein, human
  • Guanine Nucleotide Exchange Factors
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-vav
  • RNA, Small Interfering
  • VAV3 protein, human
  • Protein-Serine-Threonine Kinases
  • TRIO protein, human
  • rac1 GTP-Binding Protein