Identification of miRNA-7 by genome-wide analysis as a critical sensitizer for TRAIL-induced apoptosis in glioblastoma cells.
Identification of miRNA-7 by genome-wide analysis as a critical sensitizer for TRAIL-induced apoptosis in glioblastoma cells.
复制标题
通过全基因组分析鉴定 miRNA-7 作为 TRAIL 诱导胶质母细胞瘤细胞凋亡的关键敏化剂
DOI：
10.1093/nar/gkx317
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发表时间：
2017-06-02
影响因子：
14.9
通讯作者：
Zhang R
中科院分区：
文献类型：
--
作者：
Zhang X;Zhang X;Hu S;Zheng M;Zhang J;Zhao J;Zhang X;Yan B;Jia L;Zhao J;Wu K;Yang A;Zhang R
胶质母细胞瘤（GBM）是脑肿瘤中最致命的一种，尽管治疗方法不断改进。肿瘤坏死因子相关凋亡诱导配体（TNF-related apoptosis-inducing ligand，TRAIL）是一种很有前途的抗肿瘤药物，由于其特异性的抗肿瘤活性，有可能作为一种替代或补充疗法。为了确定调节GBM细胞对TRAIL敏感性的新途径，我们在对TRAIL诱导的凋亡具有明显敏感性的GBM细胞系中进行了microRNA的全基因组表达谱分析。我们发现miR-7的表达模式与GBM细胞对TRAIL的敏感性密切相关。此外，我们的功能获得和丧失实验表明，miR-7是GBM细胞中TRAIL诱导的凋亡的潜在致敏剂。在机制研究中，我们确定XIAP是miR-7的直接下游基因。此外，该调节轴也可以在其他类型的肿瘤细胞如肝细胞癌细胞中发挥作用。更重要的是，在异种移植模型中，TRAIL过表达的间充质干细胞中miR-7的强制表达以外来体依赖性方式增加了凋亡并抑制了肿瘤生长。总之，我们确定miR-7是TRAIL诱导的细胞凋亡的关键敏化剂，从而使其成为GBM细胞中TRAIL抗性的有希望的治疗候选物。
Abstract Glioblastoma (GBM) is still one of the most lethal forms of brain tumor despite of the improvements in treatments. TRAIL (TNF-related apoptosis-inducing ligand) is a promising anticancer agent that can be potentially used as an alternative or complementary therapy because of its specific antitumor activity. To define the novel pathways that regulate susceptibility to TRAIL in GBM cells, we performed a genome-wide expression profiling of microRNAs in GBM cell lines with the distinct sensitivity to TRAIL-induced apoptosis. We found that the expression pattern of miR-7 is closely correlated with sensitivity of GBM cells to TRAIL. Furthermore, our gain and loss of function experiments showed that miR-7 is a potential sensitizer for TRAIL-induced apoptosis in GBM cells. In the mechanistic study, we identified XIAP is a direct downstream gene of miR-7. Additionally, this regulatory axis could also exert in other types of tumor cells like hepatocellular carcinoma cells. More importantly, in the xenograft model, enforced expression of miR-7 in TRAIL-overexpressed mesenchymal stem cells increased apoptosis and suppressed tumor growth in an exosome dependent manner. In conclusion, we identify that miR-7 is a critical sensitizer for TRAIL-induced apoptosis, thus making it as a promising therapeutic candidate for TRAIL resistance in GBM cells.