Godlewski Jakub, Nowicki Michal O, Bronisz Agnieszka, Williams Shanté, Otsuki Akihiro, Nuovo Gerard, Raychaudhury Abhik, Newton Herbert B, Chiocca E Antonio, Lawler Sean
Dardinger Laboratory for Neuro-oncology and Neurosciences, Department of Neurological Surgery, The Ohio State University Medical Center and James Comprehensive Cancer Center, Columbus, Ohio 43210
Cancer Res. 2008 Nov 15;68(22):9125-30. doi: 10.1158/0008-5472.CAN-08-2629.
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.
微小RNA（miR）在各种癌症中表现出特征性的表达特征，并能深刻影响癌细胞的行为。我们对人类胶质母细胞瘤标本及其相邻的无肿瘤脑组织进行了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的明显减少。miR - 128表达在体外显著降低了胶质瘤细胞的增殖，并在体内抑制了胶质瘤异种移植瘤的生长。miR - 128通过单个miR - 128结合位点直接调控Bmi - 1 mRNA的3'非翻译区，导致Bmi - 1癌基因的表达显著下降。在一组胶质母细胞瘤患者标本中，与正常脑组织相比，Bmi - 1表达显著上调，而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)）减少和Akt磷酸化降低，以及p21(CIP1)水平上调，这与Bmi - 1下调一致。Bmi - 1也已被证明可促进干细胞自我更新；因此，我们研究了miR - 128过表达在具有胶质瘤“干细胞样”细胞特征的人类胶质瘤神经球培养物中的作用。结果表明，miR - 128与Bmi - 1下调一致，特异性地阻断了胶质瘤的自我更新。这是miR对神经干细胞自我更新因子进行特异性调控的首个实例，表明那些可能正常调节脑发育的miR作为针对胶质瘤“干细胞样”特征的重要生物学和治疗靶点。
