title: microRNA-148a is a prognostic oncomiR that targets MIG6 and BIM to regulate EGFR and apoptosis in glioblastoma.
abstract: Great interest persists in useful prognostic and therapeutic targets in glioblastoma. In this study, we report the definition of miRNA (miR)-148a as a novel prognostic oncomiR in glioblastoma. miR-148a expression was elevated in human glioblastoma specimens, cell lines, and stem cells (GSC) compared with normal human brain and astrocytes. High levels were a risk indicator for glioblastoma patient survival. Functionally, miR-148a expression increased cell growth, survival, migration, and invasion in glioblastoma cells and GSCs and promoted GSC neurosphere formation. Two direct targets of miR-148a were identified, the EGF receptor (EGFR) regulator MIG6 and the apoptosis regulator BIM, which rescue experiments showed were essential to mediate the oncogenic activity of miR-148a. By inhibiting MIG6 expression, miR-148a reduced EGFR trafficking to Rab7-expressing compartments, which includes late endosomes and lysosomes. This process coincided with reduced degradation and elevated expression and activation of EGFR. Finally, inhibition of miR-148a strongly suppressed GSC and glioblastoma xenograft growth in vivo. Taken together, our findings provide a comprehensive analysis of the prognostic value and oncogenic function of miR-148a in glioblastoma, further defining it as a potential target for glioblastoma therapy.
authors.affiliation: Authors' Affiliations: Departments of Microbiology, Immunology and Cancer Biology, Neurology, and Cancer Center, University of Virginia, Charlottesville, Virginia; Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom; and Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Jungeun
authors.initials: J
authors.lastname: Kim
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Skalski
authors.forename: Josie
authors.initials: J
authors.lastname: Hayes
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kefas
authors.forename: David
authors.initials: D
authors.lastname: Schiff
authors.forename: Benjamin
authors.initials: B
authors.lastname: Purow
authors.forename: Sarah
authors.initials: S
authors.lastname: Parsons
authors.forename: Sean
authors.initials: S
authors.lastname: Lawler
authors.forename: Roger
authors.initials: R
authors.lastname: Abounader
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics; D020691:rab GTP-Binding Proteins / Q000235:genetics; D000090802:rab7 GTP-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C550570:MIRN148 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716465:rab7 GTP-binding proteins, mouse; C512478:EGFR protein, human; D066246:ErbB Receptors; D020691:rab GTP-Binding Proteins