Abstract
Aberrant epidermal growth factor receptor (EGFR) signaling is a typical oncogenic signature in glioblastoma. Here, we show that EGFR inhibition in primary glioma stem cells (GSCs) with oncogenic EGFRvIII and EGFRvIII-transduced glioma stem-like cells promotes invasion by decreasing ID3 levels. ID3 suppresses GSC invasiveness by inhibiting p27(KIP1)-RhoA-dependent migration and MMP3 expression. Xenograft and human glioblastoma specimens show that ID3 localizes within glioblastoma cores, whereas p27(KIP1) and MMP3 are predominantly expressed in glioma cells in invasive fronts. Together, our findings show that EGFR inhibition induces GSC invasiveness by abolishing ID3-mediated inhibition of p27(KIP1) and MMP3 expression.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Movement / genetics
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Cyclin-Dependent Kinase Inhibitor p27 / metabolism*
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ErbB Receptors / antagonists & inhibitors*
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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Glioma / genetics
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Glioma / metabolism*
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Humans
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Inhibitor of Differentiation Proteins / genetics
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Inhibitor of Differentiation Proteins / metabolism*
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Matrix Metalloproteinase 3 / metabolism*
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Mice
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Neoplastic Stem Cells / metabolism*
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Quinazolines / pharmacology
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Quinazolines / toxicity
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Signal Transduction* / drug effects
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Tyrphostins / pharmacology
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Tyrphostins / toxicity
Substances
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Inhibitor of Differentiation Proteins
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Neoplasm Proteins
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Quinazolines
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Tyrphostins
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epidermal growth factor receptor VIII
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Cyclin-Dependent Kinase Inhibitor p27
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ID3 protein, human
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RTKI cpd
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ErbB Receptors
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Matrix Metalloproteinase 3