title: The neuronal microRNA miR-326 acts in a feedback loop with notch and has therapeutic potential against brain tumors.
abstract: Little is known of microRNA interactions with cellular pathways. Few reports have associated microRNAs with the Notch pathway, which plays key roles in nervous system development and in brain tumors. We previously implicated the Notch pathway in gliomas, the most common and aggressive brain tumors. While investigating Notch mediators, we noted microRNA-326 was upregulated following Notch-1 knockdown. This neuronally expressed microRNA was not only suppressed by Notch but also inhibited Notch proteins and activity, indicating a feedback loop. MicroRNA-326 was downregulated in gliomas via decreased expression of its host gene. Transfection of microRNA-326 into both established and stem cell-like glioma lines was cytotoxic, and rescue was obtained with Notch restoration. Furthermore, miR-326 transfection reduced glioma cell tumorigenicity in vivo. Additionally, we found microRNA-326 partially mediated the toxic effects of Notch knockdown. This work demonstrates a microRNA-326/Notch axis, shedding light on the biology of Notch and suggesting microRNA-326 delivery as a therapy.
authors: Division of Neuro-Oncology, Neurology Department, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
authors: Benjamin
authors: B
authors: Kefas
authors: Laurey
authors: L
authors: Comeau
authors: Desiree H
authors: DH
authors: Floyd
authors: Oleksandr
authors: O
authors: Seleverstov
authors: Jakub
authors: J
authors: Godlewski
authors: Tom
authors: T
authors: Schmittgen
authors: Jinmai
authors: J
authors: Jiang
authors: Charles G
authors: CG
authors: diPierro
authors: Yunqing
authors: Y
authors: Li
authors: E Antonio
authors: EA
authors: Chiocca
authors: Jeongwu
authors: J
authors: Lee
authors: Howard
authors: H
authors: Fine
authors: Roger
authors: R
authors: Abounader
authors: Sean
authors: S
authors: Lawler
authors: Benjamin
authors: B
authors: Purow
mesh_terms: D017209:Apoptosis / Q000235:genetics; D019390:Arrestins / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005434:Flow Cytometry / Q000379:methods; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D005910:Glioma / Q000473:pathology*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014162:Transfection / Q000379:methods; D014410:Tumor Stem Cell Assay / Q000379:methods; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; C545322:MIRN326 microRNA, human; D035683:MicroRNAs; C497761:NOTCH1 protein, human; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D000071557:beta-Arrestins