title: MicroRNA-146a inhibits glioma development by targeting Notch1.
abstract: Dysregulated epidermal growth factor receptor (EGFR) signaling through either genomic amplification or dominant-active mutation (EGFR(vIII)), in combination with the dual inactivation of INK4A/ARF and PTEN, is a leading cause of gliomagenesis. Our global expression analysis for microRNAs revealed that EGFR activation induces miR-146a expression, which is further potentiated by inactivation of PTEN. Unexpectedly, overexpression of miR-146a attenuates the proliferation, migration, and tumorigenic potential of Ink4a/Arf(-/-) Pten(-/-) Egfr(vIII) murine astrocytes. Its ectopic expression also inhibits the glioma development of a human glioblastoma cell line in an orthotopic xenograft model. Such an inhibitory function of miR-146a on gliomas is largely through downregulation of Notch1, which plays a key role in neural stem cell maintenance and is a direct target of miR-146a. Accordingly, miR-146a modulates neural stem cell proliferation and differentiation and reduces the formation and migration of glioma stem-like cells. Conversely, knockdown of miR-146a by microRNA sponge upregulates Notch1 and promotes tumorigenesis of malignant astrocytes. These findings indicate that, in response to oncogenic cues, miR-146a is induced as a negative-feedback mechanism to restrict tumor growth by repressing Notch1. Our results provide novel insights into the signaling pathways that link neural stem cells to gliomagenesis and may lead to new strategies for treating brain tumors.
authors: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
authors: Jie
authors: J
authors: Mei
authors: Robert
authors: R
authors: Bachoo
authors: Chun-Li
authors: CL
authors: Zhang
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D009368:Neoplasm Transplantation; D058953:Neural Stem Cells / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics*; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D051881:Receptor, Notch1; D025803:Tumor Suppressor Protein p14ARF; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase