Zhang Xiao, Zhang Xiang, Hu Shijie, Zheng Minhua, Zhang Jie, Zhao Jianhui, Zhang Xiaofang, Yan Bo, Jia Lintao, Zhao Jing, Wu Kaichun, Yang Angang, Zhang Rui
The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
Department of Neurosurgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China.
Nucleic Acids Res. 2017 Jun 2;45(10):5930-5944. doi: 10.1093/nar/gkx317.
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.
尽管治疗方法有所改进，但胶质母细胞瘤（GBM）仍是最致命的脑肿瘤形式之一。肿瘤坏死因子相关凋亡诱导配体（TRAIL）是一种有前景的抗癌药物，因其具有特定的抗肿瘤活性，有可能用作替代疗法或辅助疗法。为了确定调节GBM细胞对TRAIL敏感性的新途径，我们对TRAIL诱导凋亡敏感性不同的GBM细胞系进行了全基因组miRNA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，我们的功能获得和缺失实验表明，miR-7是TRAIL诱导GBM细胞凋亡的潜在致敏剂。在机制研究中，我们确定X连锁凋亡抑制蛋白（XIAP）是miR-7的直接下游基因。此外，这种调控轴也可在其他类型的肿瘤细胞如肝癌细胞中发挥作用。更重要的是，在异种移植模型中，在过表达TRAIL的间充质干细胞中强制表达miR-7以依赖外泌体的方式增加凋亡并抑制肿瘤生长。总之，我们确定miR-7是TRAIL诱导凋亡的关键致敏剂，因此使其成为GBM细胞中TRAIL耐药性的有前景的治疗候选物。
