Kefas Benjamin, Comeau Laurey, Floyd Desiree H, Seleverstov Oleksandr, Godlewski Jakub, Schmittgen Tom, Jiang Jinmai, diPierro Charles G, Li Yunqing, Chiocca E Antonio, Lee Jeongwu, Fine Howard, Abounader Roger, Lawler Sean, Purow Benjamin
Division of Neuro-Oncology, Neurology Department, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
J Neurosci. 2009 Dec 2;29(48):15161-8. doi: 10.1523/JNEUROSCI.4966-09.2009.
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.
关于微小RNA与细胞通路的相互作用，人们了解甚少。很少有报告将微小RNA与Notch通路联系起来，Notch通路在神经系统发育和脑肿瘤中起着关键作用。我们之前发现Notch通路与胶质瘤有关，胶质瘤是最常见且侵袭性最强的脑肿瘤。在研究Notch介质时，我们注意到Notch-1基因敲低后，微小RNA-326上调。这种在神经元中表达的微小RNA不仅受到Notch的抑制，还能抑制Notch蛋白和活性，表明存在一个反馈回路。微小RNA-326在胶质瘤中通过其宿主基因表达降低而下调。将微小RNA-326转染到已建立的胶质瘤细胞系和干细胞样胶质瘤细胞系中均具有细胞毒性，通过恢复Notch可实现挽救。此外，miR-326转染可降低胶质瘤细胞在体内的致瘤性。此外，我们发现微小RNA-326部分介导了Notch基因敲低的毒性作用。这项研究揭示了微小RNA-326/Notch轴，为Notch的生物学特性提供了新的见解，并提示将微小RNA-326作为一种治疗手段。
