MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators
MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators
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DOI：
10.1128/mcb.00479-08
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发表时间：
2008-09-01
影响因子：
5.3
通讯作者：
Krichevsky, Anna M.
中科院分区：
文献类型：
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作者：
Gabriely, Galina;Wurdinger, Thomas;Krichevsky, Anna M.
大量数据表明，microRNA 21（miR-21）在胶质母细胞瘤（GBM）和许多其他各种来源的肿瘤中显著升高。这种microRNA与癌发生的各个方面有关，包括细胞增殖、凋亡和迁移。我们证明，miR-21调节与胶质瘤细胞凋亡，迁移和侵袭相关的多个基因，包括RECK和TIMP 3基因，它们是恶性肿瘤的抑制因子和基质金属蛋白酶（MMPs）的抑制剂。用反义寡核苷酸特异性抑制miR-21导致RECK和TIMP 3水平升高，因此在体外和裸鼠中的人类神经胶质瘤模型中降低MMP活性。此外，在胶质瘤细胞中下调miR-21导致其迁移和侵袭能力降低。我们的数据表明，miR-21通过下调MMP抑制剂，导致MMP激活，从而促进癌细胞的侵袭性，从而促进胶质瘤恶性。我们的研究结果还表明，用特定的反义分子抑制单个oncomir，如miR-21，可以为癌症中表达失调的多种蛋白质的“生理”调节提供一种新的治疗方法。
Substantial data indicate that microRNA 21 (miR-21) is significantly elevated in glioblastoma (GBM) and in many other tumors of various origins. This microRNA has been implicated in various aspects of carcinogenesis, including cellular proliferation, apoptosis, and migration. We demonstrate that miR-21 regulates multiple genes associated with glioma cell apoptosis, migration, and invasiveness, including the RECK and TIMP3 genes, which are suppressors of malignancy and inhibitors of matrix metalloproteinases (MMPs). Specific inhibition of miR-21 with antisense oligonucleotides leads to elevated levels of RECK and TIMP3 and therefore reduces MMP activities in vitro and in a human model of gliomas in nude mice. Moreover, downregulation of miR-21 in glioma cells leads to decreases of their migratory and invasion abilities. Our data suggest that miR-21 contributes to glioma malignancy by downregulation of MMP inhibitors, which leads to activation of MMPs, thus promoting invasiveness of cancer cells. Our results also indicate that inhibition of a single oncomir, like miR-21, with specific antisense molecules can provide a novel therapeutic approach for "physiological" modulation of multiple proteins whose expression is deregulated in cancer.