title: Suppression of microRNA-9 by mutant EGFR signaling upregulates FOXP1 to enhance glioblastoma tumorigenicity.
abstract: The EGF receptor (EGFR) is amplified and mutated in glioblastoma, in which its common mutation (ΔEGFR, also called EGFRvIII) has a variety of activities that promote growth and inhibit death, thereby conferring a strong tumor-enhancing effect. This range of activities suggested to us that ΔEGFR might exert its influence through pleiotropic effectors, and we hypothesized that microRNAs might serve such a function. Here, we report that ΔEGFR specifically suppresses one such microRNA, namely miR-9, through the Ras/PI3K/AKT axis that it is known to activate. Correspondingly, expression of miR-9 antagonizes the tumor growth advantage conferred by ΔEGFR. Silencing of FOXP1, a miR-9 target, inhibits ΔEGFR-dependent tumor growth and, conversely, de-repression of FOXP1, as a consequence of miR-9 inhibition, increases tumorigenicity. FOXP1 was sufficient to increase tumor growth in the absence of oncogenic ΔEGFR signaling. The significance of these findings is underscored by our finding that high FOXP1 expression predicts poor survival in a cohort of 131 patients with glioblastoma. Collectively, these data suggest a novel regulatory mechanism by which ΔEGFR suppression of miR-9 upregulates FOXP1 to increase tumorigenicity.
authors.affiliation: Authors' Affiliations: Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, California; Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia; Department of Neurology, Washington University School of Medicine, St. Louis, Missouri; and Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: German G
authors.initials: GG
authors.lastname: Gomez
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Ciro
authors.initials: C
authors.lastname: Zanca
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Ryan
authors.initials: R
authors.lastname: Emnett
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
authors.forename: Cameron W
authors.initials: CW
authors.lastname: Brennan
authors.forename: Frank B
authors.initials: FB
authors.lastname: Furnari
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics*; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D018631:ras Proteins / Q000235:genetics
chemical_list: D051858:Forkhead Transcription Factors; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins