The neuronal microRNA miR-326 acts in a feedback loop with notch and has therapeutic potential against brain tumors.
The neuronal microRNA miR-326 acts in a feedback loop with notch and has therapeutic potential against brain tumors.
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DOI：
10.1523/jneurosci.4966-09.2009
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发表时间：
2009-12-02
期刊：
影响因子：
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通讯作者：
Purow B
中科院分区：
文献类型：
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作者：
Kefas B;Comeau L;Floyd DH;Seleverstov O;Godlewski J;Schmittgen T;Jiang J;diPierro CG;Li Y;Chiocca EA;Lee J;Fine H;Abounader R;Lawler S;Purow B
microRNA与细胞通路的相互作用知之甚少。很少有报道将microRNA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。我们先前暗示Notch通路在神经胶质瘤中，这是最常见和最具侵袭性的脑肿瘤。在研究Notch介质时，我们注意到microRNA-326在Notch-1敲低后上调。这种神经元表达的microRNA不仅被Notch抑制，而且还抑制Notch蛋白和活性，表明存在反馈回路。microRNA-326在胶质瘤中通过其宿主基因表达的降低而下调。将microRNA-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都具有细胞毒性，并且通过Notch修复获得了拯救。此外，miR-326转染降低了体内胶质瘤细胞的致瘤性。此外，我们发现microRNA-326部分介导Notch敲低的毒性作用。这项工作证明了microRNA-326/Notch轴，揭示了Notch的生物学，并表明microRNA-326递送作为一种疗法。
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 up-regulated 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 down-regulated 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.