Oncogenic miR-20a and miR-106a enhance the invasiveness of human glioma stem cells by directly targeting TIMP-2
Oncogenic miR-20a and miR-106a enhance the invasiveness of human glioma stem cells by directly targeting TIMP-2
复制标题
致癌miR-20a和miR-106a通过直接靶向TIMP-2增强人胶质瘤干细胞的侵袭性
DOI：
10.1038/onc.2014.75
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发表时间：
2015-03-12
期刊：
影响因子：
8
通讯作者：
Bian, X. W.
中科院分区：
文献类型：
--
作者：
Wang, Z.;Wang, B.;Bian, X. W.
新的证据表明，癌症干细胞（CSCs）是促进癌症侵袭和转移的细胞决定因素。然而，CSC入侵的机制仍然未知。microRNA是进化上保守的小的非编码RNA，其对于基因表达的调节至关重要，并且它们的表达在癌症中通常失调。在本研究中，我们证明了两种功能相关的microRNA，miR-20 a和-106a（miR-20 a/106 a），能够增强从胶质母细胞瘤细胞系U87和原代人脑胶质瘤标本中分离的CD 133+胶质瘤干细胞（GSC）的侵袭力。我们发现，miR-20 a/106 a在GSC中的水平显著高于定向CD 133 −胶质瘤细胞，并且与GSC的侵袭能力相关。通过生物信息学分析，我们确定了金属蛋白酶组织抑制剂-2（TIMP-2）为miR-20 a/106 a靶向基因之一。TIMP-2水平与miR-20/106表达呈负相关。miR-20 a/106 a可直接靶向TIMP-2 mRNA的3′-非翻译区（3′-UTR）。GSC中miR-20 a/106 a的敲低增加内源性TIMP-2蛋白丰度，从而抑制GSC侵袭。我们还发现，合成的脂氧合酶抑制剂Nordy通过下调miR-20 a/106 a来提高TIMP-2的表达，从而抑制GSC的侵袭力。我们的研究结果表明，miR-20 a/106 a在GSC侵袭中具有关键作用，并可作为胶质母细胞瘤治疗的靶点。
Emerging evidence has shown that cancer stem cells (CSCs) are the cellular determinants to promote cancer invasion and metastasis. However, the mechanism underlying CSC invasion remains unknown. MicroRNAs are evolutionally conserved small noncoding RNAs that are critical for the regulation of gene expression, and their expressions are often dysregulated in cancers. In the present study, we demonstrated that two functionally related microRNAs, miR-20a and-106a (miR-20a/106a), were capable of enhancing the invasiveness of CD133+ glioma stem cells (GSCs) isolated from both glioblastoma cell line U87 and primary human glioma specimens. We found that the level of miR-20a/106a in GSCs was significantly higher than that in the committed CD133− glioma cells, and correlated with the invasive capability of GSCs. By bioinformatic analysis, we identified tissue inhibitor of metalloproteinases-2 (TIMP-2) as one of the miR-20a/106a-targeted genes. TIMP-2 level correlated inversely with miR-20/106 expression. Directly targeting by miR-20a/106a on 3′-untranslation region (3′-UTR) of TIMP-2 mRNA was confirmed by 3′-UTR dual-luciferase reporter assay. Knockdown of miR-20a/106a in GSCs increased endogenous TIMP-2 protein abundance, thereby inhibiting GSC invasion. We also found that Nordy, a synthetic lipoxygenase inhibitor, inhibited GSC invasiveness by elevating the expression of TIMP-2 via downregulation of miR-20a/106a. Our results indicate that miR-20a/106a has a key role in GSC invasion and may serve as targets for treatment of glioblastoma.