MicroRNA-10b inhibition reduces E2F1-mediated transcription and miR-15/16 activity in glioblastoma.
MicroRNA-10b inhibition reduces E2F1-mediated transcription and miR-15/16 activity in glioblastoma.
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DOI：
10.18632/oncotarget.3009
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发表时间：
2015-02-28
期刊：
影响因子：
--
通讯作者：
Krichevsky AM
中科院分区：
文献类型：
--
作者：
Teplyuk NM;Uhlmann EJ;Wong AH;Karmali P;Basu M;Gabriely G;Jain A;Wang Y;Chiocca EA;Stephens R;Marcusson E;Yi M;Krichevsky AM
MicroRNA-10b(miR-10b)在胶质母细胞瘤中普遍升高，而在正常脑组织中不表达。靶向抑制miR-10b对GBM来源的细胞系具有多效性，可减少动物模型中GBM的生长，但不影响正常神经元和星形胶质细胞。这一数据增加了开发以miR-10b为靶向的GBM治疗的可能性。然而，miR-10b介导的胶质瘤细胞存活和增殖的机制尚不清楚。我们发现miR-10b的抑制对特定的胶质瘤细胞株有明显的影响。在高水平表达抑癌基因p21WAF1/Cip1的细胞中，它抑制E2F1介导的转录，导致编码S期特定蛋白、表观遗传调节物和miRNAs的多个E2F1靶基因下调(例如miR-15/16)，从而阻碍细胞周期中S期的进展。随后，miR-15/16活性降低，其许多直接靶点被解除抑制，包括破坏Cyclin E稳定的泛素连接酶FBXW7。相反，表达低水平p21或p21下调后的GBM细胞对miR-10b抑制表现出较弱的或没有E2F1反应。对肿瘤基因组图谱的比较分析表明，miR-10b和多个E2F靶基因在GBM和低级别胶质瘤中具有很强的相关性。综上所述，这些发现表明miR-10b以p21依赖的方式调控E2F1介导的GBM转录。
MicroRNA-10b (miR-10b) is commonly elevated in glioblastoma (GBM), while not expressed in normal brain tissues. Targeted inhibition of miR-10b has pleiotropic effects on GBM derived cell lines, it reduces GBM growth in animal models, but does not affect normal neurons and astrocytes. This data raises the possibility of developing miR-10b-targeting GBM therapy. However, the mechanisms contributing to miR-10b-mediated glioma cell survival and proliferation are unexplored. We found that inhibition of miR-10b has distinct effects on specific glioma cell lines. In cells expressing high levels of tumor suppressor p21WAF1/Cip1, it represses E2F1-mediated transcription, leading to down-regulation of multiple E2F1 target genes encoding for S-phase specific proteins, epigenetic modulators, and miRNAs (e.g. miR-15/16), and thereby stalling progression through the S-phase of cell cycle. Subsequently, miR-15/16 activities are reduced and many of their direct targets are de-repressed, including ubiquitin ligase FBXW7 that destabilizes Cyclin E. Conversely, GBM cells expressing low p21 level, or after p21 knock-down, exhibit weaker or no E2F1 response to miR-10b inhibition. Comparative analysis of The Cancer Genome Atlas revealed a strong correlation between miR-10b and multiple E2F target genes in GBM and low-grade glioma. Taken together, these findings indicate that miR-10b regulates E2F1-mediated transcription in GBM, in a p21-dependent fashion.
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影响因子：
64.5
作者：
Hafner M;Landthaler M;Burger L;Khorshid M;Hausser J;Berninger P;Rothballer A;Ascano M Jr;Jungkamp AC;Munschauer M;Ulrich A;Wardle GS;Dewell S;Zavolan M;Tuschl T
通讯作者：
Tuschl T
DOI：
10.1073/pnas.0800121105
发表时间：
2008-04-01
影响因子：
11.1
作者：
Calin, George A.;Cimmino, Amelia;Croce, Carlo M.
通讯作者：
Croce, Carlo M.
DOI：
10.1016/j.bbrc.2007.01.080
发表时间：
2007-03-23
影响因子：
3.1
作者：
Gu, Zhaodi;Inomata, Kenichi;Horii, Akira
通讯作者：
Horii, Akira
影响因子：
82.9
作者：
Bonci, Desiree;Coppola, Valeria;De Maria, Ruggero
通讯作者：
De Maria, Ruggero
影响因子：
5.6
作者：
Bottoni, A;Piccin, D;Uberti, ECD
通讯作者：
Uberti, ECD