title: Feedback circuitry between miR-218 repression and RTK activation in glioblastoma.
abstract: Receptor tyrosine kinase (RTK) signaling promotes the growth and progression of glioblastoma (GBM), a highly aggressive type of brain tumor. We previously reported that decreased miR-218 expression in GBM directly promotes RTK activity by increasing the expression of key RTKs and their signaling mediators, including the RTK epidermal growth factor receptor (EGFR), phospholipase C-γ1 (PLCγ1), and the kinases PIK3CA and ARAF. However, increased RTK signaling usually activates negative feedback mechanisms to maintain homeostasis. We found that decreased miR-218 expression in GBM cells also increased the expression of genes encoding additional upstream and downstream components of RTK signaling pathways, including the RTK platelet-derived growth factor receptor α (PDGFRα) and the kinases ribosomal S6 kinase 2 (RSK2) and S6 kinase 1 (S6K1), that collectively overrode the negative feedback mechanism. Furthermore, increased RTK signaling itself suppressed miR-218 expression. Mass spectrometry and DNA pull-down identified binding of signal transducer and activator of transcription 3 (STAT3) along with the transcriptional repressor BCL2-associated transcription factor 1 (BCLAF1) directly to the miR-218 locus. These data identify previously unknown feedback loops by which miR-218 repression promotes increased RTK signaling in high-grade gliomas.
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Lijoy K
authors.initials: LK
authors.lastname: Mathew
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Peiwei
authors.initials: P
authors.lastname: Huangyang
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Vera
authors.initials: V
authors.lastname: Mucaj
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Lee
authors.affiliation: INSERM U1037, Institut Claudius Regaud, 20-24 Rue du Pont Saint-Pierre, 31059 Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Skuli
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: T S Karin
authors.initials: TS
authors.lastname: Eisinger-Mathason
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Biju
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine, Institut Claudius Regaud, 31059 Toulouse, France.
authors.forename: Sriram
authors.initials: S
authors.lastname: Venneti
authors.affiliation: Department of Pathology and Laboratory Medicine, Institut Claudius Regaud, 31059 Toulouse, France.
authors.forename: Priti
authors.initials: P
authors.lastname: Lal
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lathia
authors.affiliation: Department of Stem Cell and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Keith
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA. celeste2@mail.med.upenn.edu.
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
mesh_terms: D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C119386:BCLAF1 protein, human; C547471:MIRN218 microRNA, human; D035683:MicroRNAs; D012334:RNA, Neoplasm; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D017479:Receptors, Platelet-Derived Growth Factor