title: A functional screen identifies miRs that induce radioresistance in glioblastomas.
abstract: The efficacy of radiotherapy in many tumor types is limited by normal tissue toxicity and by intrinsic or acquired radioresistance. Therefore, it is essential to understand the molecular network responsible for regulating radiosensitivity/resistance. Here, an unbiased functional screen identified four microRNAs (miR1, miR125a, miR150, and miR425) that induce radioresistance. Considering the clinical importance of radiotherapy for patients with glioblastoma, the impact of these miRNAs on glioblastoma radioresistance was investigated. Overexpression of miR1, miR125a, miR150, and/or miR425 in glioblastoma promotes radioresistance through upregulation of the cell-cycle checkpoint response. Conversely, antagonizing with antagomiRs sensitizes glioblastoma cells to irradiation, suggesting their potential as targets for inhibiting therapeutic resistance. Analysis of glioblastoma datasets from The Cancer Genome Atlas (TCGA) revealed that these miRNAs are expressed in glioblastoma patient specimens and correlate with TGFβ signaling. Finally, it is demonstrated that expression of miR1 and miR125a can be induced by TGFβ and antagonized by a TGFβ receptor inhibitor. Together, these results identify and characterize a new role for miR425, miR1, miR125, and miR150 in promoting radioresistance in glioblastomas and provide insight into the therapeutic application of TGFβ inhibitors in radiotherapy.
  
  
  CONCLUSIONS
  Systematic identification of miRs that cause radioresistance in gliomas is important for uncovering predictive markers for radiotherapy or targets for overcoming radioresistance.
authors.affiliation: Department of Radiation Oncology, Division of Genomic Stability and DNA Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Department of Internal Medicine A, Medical University of Greifswald, Ferdinand-Sauerbruchstrasse, Greifswald, Germany.
authors.forename: Patryk
authors.initials: P
authors.lastname: Moskwa
authors.affiliation: Department of Neurosurgery, Baylor College of Medicine and M Anderson Cancer Center, Houston, Texas.
authors.forename: Pascal O
authors.initials: PO
authors.lastname: Zinn
authors.affiliation: Department of Radiation Oncology, Division of Genomic Stability and DNA Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Young Eun
authors.initials: YE
authors.lastname: Choi
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Sachet A
authors.initials: SA
authors.lastname: Shukla
authors.affiliation: Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Fendler
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology, Moores Cancer Center, Division of Neurosurgery, University of California San Diego, San Diego, California.
authors.forename: Clark C
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Yale Stem Cell Center and Department of Genetics, Yale University, New Haven, Connecticut.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts. Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.affiliation: Department of Cell, Developmental, and Integrative Biology University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Anita
authors.initials: A
authors.lastname: Hjelmeland
authors.affiliation: Department of Radiation Oncology, Division of Genomic Stability and DNA Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. dipanjan_chowdhury@dfci.harvard.edu.
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Chowdhury
mesh_terms: D059447:Cell Cycle Checkpoints / Q000528:radiation effects; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D005909:Glioblastoma / Q000235:genetics* / Q000532:radiotherapy; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D011836:Radiation Tolerance; D015398:Signal Transduction / Q000528:radiation effects; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D016212:Transforming Growth Factor beta; C544547:MIRN1 microRNA, human; C531888:MIRN125 microRNA, human; C533097:MIR150, human; C555677:MIRN425 microRNA, human