Department of Experimental Medicine, Sapienza University, Viale Regina Elena, 291, 00161 Rome, Italy.
Department of Molecular Medicine, Sapienza University, 00161 Rome, Italy.
Int J Mol Sci. 2017 Dec 17;18(12):2742. doi: 10.3390/ijms18122742.
The mechanisms by which microRNAs control pediatric high-grade gliomas (pHGGs) have yet to be fully elucidated. Our studies of patient-derived pHGG tissues and of the pHGG cell line KNS42 revealed down-regulation in these tumors of three microRNAs, specifically miR-107, miR-181c, and miR-29a-3p. This down-regulation increases the proliferation of KNS42 cells by de-repressing expression of the Notch2 receptor (Notch2), a validated target of miR-107 and miR-181c and a putative target of miR-29a-3p. Inhibition (either pharmacologic or genetic) of Notch2 or re-expression of the implicated microRNAs (all three combined but also individually) significantly reduced KNS42 cell proliferation. These findings suggest that Notch2 pathway activation plays a critical role in pHGGs growth and reveal a direct epigenetic mechanism that controls Notch2 expression, which could potentially be targeted by novel forms of therapy for these childhood tumors characterized by high-morbidity and high-mortality.
microRNAs 控制小儿高级别神经胶质瘤（pHGG）的机制尚未完全阐明。我们对患者来源的 pHGG 组织和 pHGG 细胞系 KNS42 的研究表明，这三种 microRNAs（miR-107、miR-181c 和 miR-29a-3p）在这些肿瘤中存在下调。这种下调通过去抑制 Notch2 受体（Notch2）的表达来增加 KNS42 细胞的增殖，Notch2 是 miR-107 和 miR-181c 的有效靶点，也是 miR-29a-3p 的潜在靶点。Notch2 的抑制（无论是药理学还是遗传学）或受影响 microRNAs 的重新表达（全部三个组合，也可以单独）显著降低了 KNS42 细胞的增殖。这些发现表明 Notch2 通路的激活在 pHGG 的生长中起着关键作用，并揭示了一种直接的表观遗传机制来控制 Notch2 的表达，这可能成为这些具有高发病率和高死亡率的儿童肿瘤的新型治疗方法的靶点。
