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Autocrine Platelet-Derived Growth Factor–Dependent Gene Expression in Glioblastoma Cells Is Mediated Largely by Activation of the Transcription Factor Sterol Regulatory Element Binding Protein and Is Associated with Altered Genotype and Patient Survival in Human Brain Tumors

¹ Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine and ² Department of Statistics, University of Kentucky, Lexington, Kentucky and ³ Department of Pathology, Cancer Center and Neurosurgical Service, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

Requests for reprints: David Kaetzel, Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536-0084. Phone: 859-257-6558; Fax: 859-323-1981; E-mail: dmkaetz{at}uky.edu.

A complex profile of gene expression elicited by autocrine platelet-derived growth factor (PDGF) signaling was identified in U87 MG glioblastoma cells by microarray analysis. The most striking pattern observed was a PDGF-dependent activation of at least 25 genes involved with biosynthesis and/or uptake of cholesterol and isoprenoids, including mevalonate pyrophosphate decarboxylase, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase, HMG-CoA reductase, and low-density lipoprotein receptor. Activity of the HMG-CoA synthase promoter was induced by autocrine PDGF activity as indicated by significant reductions following forced expression of dominant-negative PDGF-A (88%) or treatment with the PDGF receptor antagonist CT52923 (50%). Induction of the HMG-CoA synthase promoter required a binding site for sterol regulatory element binding proteins (SRE-BP), consistent with a key role for these transcription factors in the induction of this gene network. Neither proteolytic activation nor nuclear localization of SRE-BP was affected by disruption of the PDGF autocrine loop, indicating that PDGF signaling is required for other signaling events involved in activation of SRE-BP target genes. Analysis of an expression databank derived from human glial tumors (n = 77) identified a subgroup exhibiting a profile consistent with PDGF dependence, including increased expression of SRE-BP target genes. This subgroup displayed an absence of epidermal growth factor receptor gene amplification, decreased incidence of allelic loss of 10q, increased frequency of TP53 mutations and allelic losses of 1p and 19q, and longer patient survival. This study identifies genes associated with oncogenic activity of PDGF and provides important insights into biomarkers and therapeutic targets in malignant gliomas.

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