Human glioma growth is controlled by microRNA-10b.
Human glioma growth is controlled by microRNA-10b.
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DOI：
10.1158/0008-5472.can-10-3568
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发表时间：
2011-05-15
期刊：
影响因子：
11.2
通讯作者：
Krichevsky AM
中科院分区：
文献类型：
--
作者：
Gabriely G;Yi M;Narayan RS;Niers JM;Wurdinger T;Imitola J;Ligon KL;Kesari S;Esau C;Stephens RM;Tannous BA;Krichevsky AM
microRNA（miRNA）表达谱研究揭示了恶性脑肿瘤胶质母细胞瘤中大量miRNA的失调。这些miRNA在胶质瘤发生中的分子功能主要是未知的。我们发现，抑制miR-10 b，一种在人脑中不表达并在低级和高级胶质瘤中强烈上调的miRNA，通过细胞周期阻滞和凋亡减少胶质瘤细胞生长。这些细胞反应由miR-10 b的直接靶点的增强表达介导，包括BCL 2L 11/Bim、TFAP 2C/AP-2γ、CDKN 1A/p21和CDKN 2A/p16，其通常保护细胞免受不受控制的生长。对癌症基因组图谱（TCGA）表达数据集的分析揭示了人类胶质母细胞瘤中维持细胞生长的许多基因与miR-10 b水平之间的强正相关性，而促凋亡基因与miR-10 b的表达反相关。此外，与具有低miR-10水平的患者相比，表达高水平miR-10家族成员的胶质母细胞瘤患者的存活率显著降低，表明miR-10可能有助于体内胶质瘤生长。最后，在人神经胶质瘤的小鼠模型中抑制miR-10 b导致肿瘤生长的显著减少。总之，我们的实验验证了miR-10 b在胶质瘤发生中的重要作用，揭示了miR-10 b介导的调控的新机制，并表明其未来用作胶质瘤治疗靶点的可能性。
MicroRNA (miRNA) expression profiling studies revealed a number of miRNAs dysregulated in the malignant brain tumor, glioblastoma. Molecular functions of these miRNAs in gliomagenesis are mainly unknown. We show that inhibition of miR-10b, a miRNA not expressed in human brain and strongly up-regulated in both low-grade and high-grade gliomas, reduces glioma cell growth by cell cycle arrest and apoptosis. These cellular responses are mediated by augmented expression of the direct targets of miR-10b, including BCL2L11/Bim, TFAP2C/AP-2γ, CDKN1A/p21, and CDKN2A/p16, which normally protect cells from uncontrolled growth. Analysis of The Cancer Genome Atlas (TCGA) expression dataset reveals a strong positive correlation between numerous genes sustaining cellular growth and miR-10b levels in human glioblastomas, while pro-apoptotic genes anti-correlate with the expression of miR-10b. Furthermore, survival of glioblastoma patients expressing high levels of miR-10 family members is significantly reduced in comparison to patients with low miR-10 levels, indicating that miR-10 may contribute to glioma growth in vivo. Finally, inhibition of miR-10b in a mouse model of human glioma results in significant reduction of tumor growth. Altogether, our experiments validate an important role of miR-10b in gliomagenesis, reveal a novel mechanism of miR-10b-mediated regulation, and suggest the possibility of its future use as a therapeutic target in gliomas.