Therapeutic potential of targeting microRNA-10b in established intracranial glioblastoma: first steps toward the clinic.
Therapeutic potential of targeting microRNA-10b in established intracranial glioblastoma: first steps toward the clinic.
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DOI：
10.15252/emmm.201505495
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发表时间：
2016-03-01
影响因子：
11.1
通讯作者：
Krichevsky AM
中科院分区：
文献类型：
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作者：
Teplyuk NM;Uhlmann EJ;Gabriely G;Volfovsky N;Wang Y;Teng J;Karmali P;Marcusson E;Peter M;Mohan A;Kraytsberg Y;Cialic R;Chiocca EA;Godlewski J;Tannous B;Krichevsky AM
microRNA-10 b（miR-10 b）是一种独特的致癌miRNA，在所有GBM亚型中高度表达，而在大脑的正常神经胶质细胞中不存在。miR-10 b抑制会强烈损害培养的胶质瘤细胞（包括胶质瘤起始干细胞样细胞（GSC））的增殖和存活。尽管先前已经鉴定了几种miR-10 b靶点，但赋予GSC的miR-10 b持续活力的共同机制尚不清楚。在这里，我们证明了在异质性GSC中，miR-10 b调节细胞周期和选择性剪接，通常通过其靶基因（包括MBNL 1 - 3，SART 3和RSRC 1）的5′ UTR进行非经典靶向。我们进一步评估了无胸腺和免疫活性小鼠颅内人GSC来源的异种移植物和鼠GL 261同种异体移植物模型中miR-10 b的抑制。已经探索了miR-10 b反义寡核苷酸抑制剂（阿索）的三种递送途径，即直接瘤内注射、连续渗透递送和全身静脉内注射。在所有情况下，用miR-10 b阿索治疗导致靶点的去抑制，并减弱已建立的颅内GBM的生长和进展。通过局部或全身途径给予阿索后，未观察到显著的全身毒性。我们的研究结果表明，miR-10 b是开发针对所有GBM亚型的靶向治疗的有希望的候选者。
MicroRNA‐10b (miR‐10b) is a unique oncogenic miRNA that is highly expressed in all GBM subtypes, while absent in normal neuroglial cells of the brain. miR‐10b inhibition strongly impairs proliferation and survival of cultured glioma cells, including glioma‐initiating stem‐like cells (GSC). Although several miR‐10b targets have been identified previously, the common mechanism conferring the miR‐10b‐sustained viability of GSC is unknown. Here, we demonstrate that in heterogeneous GSC, miR‐10b regulates cell cycle and alternative splicing, often through the non‐canonical targeting via 5′UTRs of its target genes, including MBNL1‐3, SART3, and RSRC1. We have further assessed the inhibition of miR‐10b in intracranial human GSC‐derived xenograft and murine GL261 allograft models in athymic and immunocompetent mice. Three delivery routes for the miR‐10b antisense oligonucleotide inhibitors (ASO), direct intratumoral injections, continuous osmotic delivery, and systemic intravenous injections, have been explored. In all cases, the treatment with miR‐10b ASO led to targets’ derepression, and attenuated growth and progression of established intracranial GBM. No significant systemic toxicity was observed upon ASO administration by local or systemic routes. Our results indicate that miR‐10b is a promising candidate for the development of targeted therapies against all GBM subtypes.