Targeting of the Bmi-1 Oncogene/Stem Cell Renewal Factor by MicroRNA-128 Inhibits Glioma Proliferation and Self-Renewal
Targeting of the Bmi-1 Oncogene/Stem Cell Renewal Factor by MicroRNA-128 Inhibits Glioma Proliferation and Self-Renewal
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DOI：
10.1158/0008-5472.can-08-2629
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发表时间：
2008-11-15
期刊：
影响因子：
11.2
通讯作者：
Lawler, Sean
中科院分区：
文献类型：
--
作者：
Godlewski, Jakub;Nowicki, Michal O.;Lawler, Sean
MicroRNAs(MiR)在各种癌症中显示出独特的表达特征，并可以深刻地影响癌细胞的行为。我们对人脑胶质母细胞瘤标本和邻近无瘤脑标本进行了miR表达谱分析。这揭示了几个显著的变化，包括肿瘤样本中miR-128的显著减少。MIR-128的表达显著抑制了胶质瘤细胞的体外增殖和体内移植瘤的生长。MIR-128通过单个miR-128结合位点直接调节BMI-1mRNA3‘非翻译区，导致BMI-1癌基因表达显著降低。在一组胶质母细胞瘤患者样本中，与正常脑相比，BMI-1表达显著上调，miR-128表达下调。Bmi-1通过表观遗传染色质修饰在某些基因的表观遗传沉默中发挥作用。我们发现miR-128表达导致组蛋白甲基化(H3K27me(3))和Akt磷酸化降低，p21(CIP1)水平上调，与BMI-1下调一致。Bmi-1也被证明可以促进干细胞的自我更新；因此，我们研究了miR-128在具有胶质瘤干细胞特征的人脑胶质瘤神经球培养中的过表达的影响。这表明miR-128特异性地阻断了胶质瘤的自我更新，这与BMI-1下调一致。这是第一个通过miR对神经干细胞自我更新因子进行特定调控的例子，这意味着通常可能调节大脑发育的miR是针对胶质瘤的“干细胞样”特征的重要生物和治疗靶点。[癌症资源2008；68(22)：9125-30]
MicroRNAs (miR) show characteristic expression signatures in various cancers and can profoundly affect cancer cell behavior. We carried out miR expression profiling of human glioblastoma specimens versus adjacent brain devoid of tumor. This revealed several significant alterations, including a pronounced reduction of miR-128 in tumor samples. miR-128 expression significantly reduced glioma cell proliferation in vitro and glioma xenograft growth in vivo. miR-128 caused a striking decrease in expression of the Bmi-1 oncogene, by direct regulation of the Bmi-1 mRNA 3'-untranslated region, through a single miR-128 binding site. In a panel of patient glioblastoma specimens, Bmi-1 expression was significantly up-regulated and miR-128 was down-regulated compared with normal brain. Bmi-1 functions in epigenetic silencing of certain genes through epigenetic chromatin modification. We found that miR-128 expression caused a decrease in histone methylation (H3K27me(3)) and Akt phosphorylation, and up-regulation of p21(CIP1) levels, consistent with Bmi-1 down-regulation. Bmi-1 has also been shown to promote stem cell self-renewal; therefore, we investigated the effects of miR-128 overexpression in human glioma neurosphere cultures, possessing features of glioma "stem-like" cells. This showed that miR-128 specifically blocked glioma self-renewal consistent with Bmi-1 down-regulation. This is the first example of specific regulation by a miR of a neural stem cell self-renewal factor, implicating miRs that may normally regulate brain development as important biological and therapeutic targets against the "stem cell-like" characteristics of glioma. [Cancer Res 2008;68(22):9125-30]