MicroRNA-21 knockdown disrupts glioma growth In vivo and displays synergistic cytotoxicity with neural precursor cell-delivered S-TRAIL in human gliomas
MicroRNA-21 knockdown disrupts glioma growth In vivo and displays synergistic cytotoxicity with neural precursor cell-delivered S-TRAIL in human gliomas
复制标题
DOI：
10.1158/0008-5472.can-07-1045
复制
发表时间：
2007-10-01
期刊：
影响因子：
11.2
通讯作者：
Shah, Khalid
中科院分区：
文献类型：
--
作者：
Corsten, Maarten F.;Miranda, Rafael;Shah, Khalid
尽管新的胶质瘤治疗方法的发展允许肿瘤靶向的原位输送细胞毒药物，但肿瘤对细胞凋亡的抵抗仍然是有效治疗的关键障碍。越来越多的证据表明，microRNAs(MiRNA)可能在肿瘤的发生、控制细胞的增殖和凋亡中发挥重要作用。在胶质瘤中，microRNA-21(miR-21)的水平被报道升高，并且它们的下调与细胞凋亡活性的增加有关。我们推测，抑制miR-21可能使胶质瘤对细胞毒肿瘤治疗增敏。通过使用锁定核酸-反义iR-21寡核苷酸、双峰成像载体和表达细胞毒剂肿瘤坏死因子相关凋亡诱导配体的分泌型变体的神经前体细胞(S-TRAIL)，我们发现联合抑制miR-21和鼻咽癌-S-TRAIL可以协同增加caspase活性，并显著降低体外培养的人脑胶质瘤细胞的存活率。这种现象在体内持续存在，因为我们观察到在NiPC-S-TRAIL存在的情况下，LNA-anttimiR-21治疗的胶质瘤在小鼠大脑中完全根除。我们的结果揭示了miR-21拮抗小鼠脑胶质瘤模型的有效性，并提示miR-21可作为治疗干预的靶点。此外，我们的发现为开发使用miRNA调节和细胞毒肿瘤治疗的联合疗法提供了基础。
Despite the development of new glioma therapies that allow for tumor-targeted in situ delivery of cytotoxic drugs, tumor resistance to apoptosis remains a key impediment to effective treatment. Mounting evidence indicates that microRNAs (miRNA) might play a fundamental role in tumorigenesis, controlling cell proliferation and apoptosis. In gliomas, microRNA-21 (miR-21) levels have been reported to be elevated and their knockdown is associated with increased apoptotic activity. We hypothesized that suppression of miR-21 might sensitize gliomas for cytotoxic tumor therapy. With the use of locked nucleic acid (LNA)-antimiR-21 oligonucleotides, bimodal imaging vectors, and neural precursor cells (NPC) expressing a secretable variant of the cytotoxic agent tumor necrosis factor-related apoptosis inducing ligand (S-TRAIL), we show that the combined suppression of miR-21 and NPC-S-TRAIL leads to a synergistic increase in caspase activity and significantly decreased cell viability in human glioma cells in vitro. This phenomenon persists in vivo, as we observed complete eradication of LNA-antimiR-21-treated gliomas subjected to the presence of NIPC-S-TRAIL in the murine brain. Our results reveal the efficacy of miR-21 antagonism in murine glioma models and implicate miR-21 as a target for therapeutic intervention. Furthermore, our findings provide the basis for developing combination therapies using miRNA modulation and cytotoxic tumor therapies.