The Inhibitory Effect Of Pten By Its Protein Phosphatase Activity On The Invasion Of Glioma Cells With EGFRvâ…¢ Expression

Glioblastoma multiform (GBM), a severe type of primary brain tumor, is lethal because it infiltrates the surrounding normal tissue. EGFR is genomically amplified in 40~50% of GBMs and often followed by gene alterations. The most frequently found alteration is a deletion encompassing exons 2-7, EGFRvâ…¢, which is ligand-independent, constitutively activated. It is generated by gene rearrangement or aberrant mRNA splice. EGFRvâ…¢ promotes the tumorigenicity of glioma cells in vivo by enhancing cell proliferation and eliminating cell death. EGFRvâ…¢-positive tumors have also been associated with poorer prognosis and shorter life expectancies. Recently, it has been suggested that EGFRvâ…¢ could enhance cell invasion probably by activating ERK, extracellular matrix components, metalloproteases et al.Tumors are diseases with variant changes of genes even when they originate from the same kind of organ or tissue. Therefore, it is essential to subdivide cancer by the combination of gene changes. PTEN mutation has been found in 20-40% of malignant gliomas. EGFRvIII was reported to coexpress in 13% or 26% of the PTEN-deficient EGFR-expressing tumor.PTEN has been shown to interact directly with FAK and reduce its tyrosine phosphorylation levels to inhibit cell spreading, migration and invasion. But, could PTEN inhibit cell invasion even in the presence of strong pro-invasive signals provided by constitutive EGFR activity.We established a glioma cell line, U87AEGFR with EGFRvâ…¢ expression but missing PTEN. Agarose drop assay and Transwell cell invasion assay showed that EGFRvIII increased glioma cell migration and invasion. When wtPTEN and PTEN(G129E) was restorated in U87AEGFR, scratch-wound assay and Transwell cell invasion assay showed that PTEN inhibited glioma cell migration and invasion in vitro, regardless of constitutive EGFR. But, PTEN(C124A) did not. Therefore, we inferred that the protein phophatse activity of PTEN could be necessary to inhibit cell invasion. Further studies found that...