The guanine nucleotide exchange factors trio, Ect2, and Vav3 mediate the invasive behavior of glioblastoma.
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.
Salhia
Bodour
B
Arthur and Sonia Labatt Brain Tumor Research Centre, Cancer and Cell Biology Division, The Hospital for Sick Children, the University of Toronto, Toronto, Canada.
Tran
Nhan L
NL
Chan
Amanda
A
Wolf
Amparo
A
Nakada
Mitsutoshi
M
Rutka
Fiona
F
Ennis
Matthew
M
McDonough
Wendy S
WS
Berens
Michael E
ME
Symons
Marc
M
Rutka
James T
JT
D000818:Animals; D001921:Brain / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D030561:Databases, Nucleic Acid; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000473:pathology / Q000503:physiopathology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009361:Neoplasm Invasiveness; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
C489850:ECT2 protein, human; D020662:Guanine Nucleotide Exchange Factors; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D034741:RNA, Small Interfering; C496621:VAV3 protein, human; D017346:Protein Serine-Threonine Kinases; C099628:TRIO protein, human; D020830:rac1 GTP-Binding Protein