MiR-139 Inhibits Mcl-1 Expression and Potentiates TMZ-Induced Apoptosis in Glioma
MiR-139 Inhibits Mcl-1 Expression and Potentiates TMZ-Induced Apoptosis in Glioma
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DOI：
10.1111/cns.12089
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发表时间：
2013-07-01
影响因子：
5.5
通讯作者：
Jiang, Chuan-Lu
中科院分区：
文献类型：
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作者：
Li, Rui-Yan;Chen, Ling-Chao;Jiang, Chuan-Lu
Mcl-1是Bcl-2家族的抗凋亡成员，在人胶质母细胞瘤中过表达，赋予肿瘤细胞存活优势。其失调的机制尚未阐明。在这项研究中，我们探讨了参与的micro-RNA作为内源性序列特异性抑制基因表达。方法和结果使用计算和TCGA分析，我们确定了miR-139在胶质母细胞瘤中与人脑组织相比下调，以及在Mcl-1 mRNA中具有推定的靶位点。miR-139的过表达导致胶质瘤中Mcl-1表达的明显降低。报告基因分析揭示了涉及miR-139和Mcl-1的3-非翻译区的直接转录后调控。miR-139低表达的人脑胶质瘤组织中Mcl-1蛋白的表达高于高表达的人脑胶质瘤组织，表明低miR-139有助于Mcl-1的过表达。此外，miR-139的上调抑制了增殖并增强了替莫唑胺（TMZ）诱导的凋亡。最后，我们观察到与miR-139转染相比，Mcl-1敲低导致类似的效果。结论miR-139在胶质瘤中协同抗肿瘤药物TMZ负调控Mcl-1并诱导细胞凋亡。
Aims Mcl-1, an antiapoptotic member of the Bcl-2 family, is overexpressed in human glioblastoma, conferring a survival advantage to tumor cells. The mechanisms underlying its dysregulation have not been clarified. In this study, we explored the involvement of micro-RNAs that acted as endogenous sequence-specific suppressors of gene expression. Methods and results Using computational and TCGA analysis, we identified miR-139 as being downregulated in glioblastoma in comparison with human brain tissue, as well as possessing a putative target site in Mcl-1 mRNA. Overexpression of miR-139 led to a clear decrease in Mcl-1 expression in gliomas. Reporter assays revealed direct post-transcriptional regulation involving miR-139 and the 3-untranslated region of Mcl-1. Human glioma tissues with low expression of miR-139 displayed higher expression of Mcl-1 protein than those with high expression, suggesting that low miR-139 contributes to Mcl-1 overexpression. In addition, upregulation of miR-139 suppressed the proliferation and enhanced temozolomide (TMZ)-induced apoptosis. Finally, we observed that Mcl-1 knockdown resulted in similar effects compared with miR-139 transfection. Conclusion Our results suggested that miR-139 negatively regulated Mcl-1 and induced apoptosis in cooperation with an anticancer drug TMZ in glioma.