The neuronal microRNA miR-326 acts in a feedback loop with notch and has therapeutic potential against brain tumors.
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.
Kefas
Benjamin
B
Division of Neuro-Oncology, Neurology Department, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
Comeau
Laurey
L
Floyd
Desiree H
DH
Seleverstov
Oleksandr
O
Godlewski
Jakub
J
Schmittgen
Tom
T
Jiang
Jinmai
J
diPierro
Charles G
CG
Li
Yunqing
Y
Chiocca
E Antonio
EA
Lee
Jeongwu
J
Fine
Howard
H
Abounader
Roger
R
Lawler
Sean
S
Purow
Benjamin
B
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
D019390:Arrestins; C545322:MIRN326 microRNA, human; D035683:MicroRNAs; C497761:NOTCH1 protein, human; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D000071557:beta-Arrestins