Targeting the RAS/MAPK pathway with miR-181a in acute myeloid leukemia.
Targeting the RAS/MAPK pathway with miR-181a in acute myeloid leukemia.
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DOI：
10.18632/oncotarget.11150
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发表时间：
2016-09-13
期刊：
影响因子：
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通讯作者：
Marcucci G
中科院分区：
文献类型：
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作者：
Huang X;Schwind S;Santhanam R;Eisfeld AK;Chiang CL;Lankenau M;Yu B;Hoellerbauer P;Jin Y;Tarighat SS;Khalife J;Walker A;Perrotti D;Bloomfield CD;Wang H;Lee RJ;Lee LJ;Marcucci G
microRNA表达的失调经常发生在急性髓细胞白血病（AML）中。较低的miR-181 a表达与更差的结果相关，但miR-181 a介导这种效应的确切机制仍然难以捉摸。RAS通路的异常激活有助于髓系白血病的发生。在这里，我们报告了miR-181 a直接结合3′-非翻译区（UTR）;下调KRAS，NRAS和MAPK 1;并减少AML生长。使用转铁蛋白靶向脂质聚合物纳米颗粒（NP）将miR-181 a模拟物递送至靶向AML细胞增加了成熟miR-181 a;下调了KRAS、NRAS和MAPK 1;并导致下游RAS效应物的磷酸化降低。NP介导的miR-181 a上调导致增殖减少、集落形成受损和对化疗的敏感性增加。KRAS、NRAS和MAPK 1的异位表达减弱了miR-181 a模拟物的抗白血病活性，从而验证了AML中失调的miR-181 a-RAS网络的相关性。最后，在鼠AML模型中用miR-181 a-NP治疗导致与用scramble-NP对照治疗的小鼠相比更长的存活。这些数据支持通过miR-181 a模拟物靶向RAS-MAPK通路代表了AML和可能用于其他RAS驱动的癌症的新的有希望的治疗方法。
Deregulation of microRNAs' expression frequently occurs in acute myeloid leukemia (AML). Lower miR-181a expression is associated with worse outcomes, but the exact mechanisms by which miR-181a mediates this effect remain elusive. Aberrant activation of the RAS pathway contributes to myeloid leukemogenesis. Here, we report that miR-181a directly binds to 3′-untranslated regions (UTRs); downregulates KRAS, NRAS and MAPK1; and decreases AML growth. The delivery of miR-181a mimics to target AML cells using transferrin-targeting lipopolyplex nanoparticles (NP) increased mature miR-181a; downregulated KRAS, NRAS and MAPK1; and resulted in decreased phosphorylation of the downstream RAS effectors. NP-mediated upregulation of miR-181a led to reduced proliferation, impaired colony formation and increased sensitivity to chemotherapy. Ectopic expression of KRAS, NRAS and MAPK1 attenuated the anti-leukemic activity of miR-181a mimics, thereby validating the relevance of the deregulated miR-181a-RAS network in AML. Finally, treatment with miR-181a-NP in a murine AML model resulted in longer survival compared to mice treated with scramble-NP control. These data support that targeting the RAS-MAPK-pathway by miR-181a mimics represents a novel promising therapeutic approach for AML and possibly for other RAS-driven cancers.