Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Cancer Res. 2020 Apr 15;80(8):1644-1655. doi: 10.1158/0008-5472.CAN-19-1624. Epub 2020 Feb 24.
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 and 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 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.
多形性胶质母细胞瘤（GBM）和其他实体恶性肿瘤是异质的，包含表现出干细胞样特征的肿瘤细胞亚群。我们最近的研究结果表明了一种去分化机制，其中重编程转录因子 Oct4 和 Sox2 通过差异调节 miRNA 的亚群来驱动胶质母细胞瘤中的干细胞样表型。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，我们确定了 miR-486-5p 是 Sox2 诱导的 miRNA，其靶向肿瘤抑制基因 和 ，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，并且在神经球系中直接由 Sox2 在神经胶质瘤细胞系和患者来源的神经球中诱导。强制表达 miR-486-5p 增强了 GBM 神经球的自我更新能力，而内源性 miR-486-5p 的抑制通过上调促凋亡蛋白 BIM 并通过依赖于 PTEN 的机制诱导细胞死亡来激活 PTEN 和 FoxO1。此外，使用先进的纳米颗粒制剂将 miR-486-5p 反义寡核苷酸递送至预先建立的原位 GBM 神经球衍生异种移植物中，可减少肿瘤大小，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的、可治疗的 Sox2：miR-486-5p 轴，该轴通过抑制肿瘤抑制途径来增强 GBM 干细胞的存活。意义：这项研究确定了一个新的轴，该轴将癌症细胞干性的核心转录驱动因子与 miR-486-5p 依赖性调节肿瘤抑制基因联系起来，这些基因反馈调节调节胶质瘤干细胞的存活。
