A Sox2:miR-486-5p Axis Regulates Survival of GBM Cells by Inhibiting Tumor Suppressor Networks
A Sox2:miR-486-5p Axis Regulates Survival of GBM Cells by Inhibiting Tumor Suppressor Networks
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DOI：
10.1158/0008-5472.can-19-1624
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发表时间：
2020-04-15
期刊：
影响因子：
11.2
通讯作者：
Laterra, John
中科院分区：
文献类型：
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作者：
Lopez-Bertoni, Hernando;Kotchetkov, Ivan S.;Laterra, John
多形性胶质母细胞瘤 (GBM) 和其他实体恶性肿瘤具有异质性，并且包含表现出干细胞样特征的肿瘤细胞亚群。我们最近的发现指出了一种去分化机制，通过该机制，重编程转录因子 Oct4 和 Sox2 驱动胶质母细胞瘤中的干细胞表型，部分是通过差异调节 miRNA 子集来实现的。目前，重编程转录因子和 miRNA 协调癌症干细胞肿瘤增殖能力的分子机制尚不清楚。在这项研究中，我们鉴定出 miR-486-5p 是 Sox2 诱导的 miRNA，它靶向肿瘤抑制基因 PTEN 和 FoxO1，并调节 GBM 干细胞样细胞。 miR-486-5p 与 GBM 干细胞表型和 Sox2 表达相关，并在神经胶质瘤细胞系和患者来源的神经球中直接被 Sox2 诱导。 miR-486-5p的强制表达增强了GBM神经球的自我更新能力，抑制内源性miR-486-5p激活PTEN和FoxO1，并通过PTEN依赖性机制上调促凋亡蛋白BIM诱导细胞死亡。此外，使用先进的纳米颗粒制剂将 miR-486-5p antagomir 递送至预先建立的原位 GBM 神经球衍生异种移植物中，可减小体内肿瘤大小并增强对电离辐射的细胞毒性反应。这些结果定义了一个以前未被识别且可治疗靶向的 Sox2:miR-486-5p 轴，该轴通过抑制肿瘤抑制通路来增强 GBM 干细胞的存活。意义：这项研究确定了一个新的轴，它将癌细胞干性的核心转录驱动因素与 miR-486-5p 依赖性肿瘤抑制基因调节联系起来，从而反馈调节神经胶质瘤干细胞的存活。
Glioblastoma multiforme (GBM) and other solid malignancies are heterogeneous and contain subpopulations of tumor cells that exhibit stem-like features. Our recent findings point to a dedifferentiation mechanism by which reprogramming transcription factors Oct4 and Sox2 drive the stem-like phenotype in glioblastoma, in part, by differentially regulating subsets of miRNAs. Currently, the molecular mechanisms by which reprogramming transcription factors and miRNAs coordinate cancer stem cell tumor-propagating capacity are unclear. In this study, we identified miR-486-5p as a Sox2-induced miRNA that targets the tumor suppressor genes PTEN and FoxO1 and regulates the GBM stem-like cells. miR-486-5p associated with the GBM stem cell phenotype and Sox2 expression and was directly induced by Sox2 in glioma cell lines and patient-derived neurospheres. Forced expression of miR-486-5p enhanced the self-renewal capacity of GBM neurospheres, and inhibition of endogenous miR-486-5p activated PTEN and FoxO1 and induced cell death by upregulating proapoptotic protein BIM via a PTEN-dependent mechanism. Furthermore, delivery of miR-486-5p antagomirs to preestablished orthotopic GBM neurosphere-derived xenografts using advanced nanoparticle formulations reduced tumor sizes in vivo and enhanced the cytotoxic response to ionizing radiation. These results define a previously unrecognized and therapeutically targetable Sox2:miR-486-5p axis that enhances the survival of GBM stem cells by repressing tumor suppressor pathways.Significance: This study identifies a novel axis that links core transcriptional drivers of cancer cell stemness to miR-486-5p-dependent modulation of tumor suppressor genes that feeds back to regulate glioma stem cell survival.