The Neuronal MicroRNA miR-326 Acts in a Feedback Loop with Notch and Has Therapeutic Potential against Brain Tumors

Benjamin Kefas(University of Virginia Health System), Laurey Comeau(University of Virginia Health System), Desiree H. Floyd(University of Virginia Health System), Oleksandr Seleverstov(University of Virginia Health System), Jakub Godlewski(The Ohio State University Wexner Medical Center), Tom Schmittgen(The Ohio State University), Jinmai Jiang(The Ohio State University), Charles G. diPierro(University of Virginia Health System), Yunqing Li(Kennedy Krieger Institute), E. Antonio Chiocca(The Ohio State University Wexner Medical Center), Jeongwu Lee(National Institutes of Health), Howard A. Fine(National Institutes of Health), Roger Abounader(University of Virginia Health System), Sean Lawler(The Ohio State University Wexner Medical Center), Benjamin Purow(University of Virginia Health System)
Journal of Neuroscience
December 2, 2009
10.1523/jneurosci.4966-09.2009
Cited by 217Open Access
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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.

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