Nkx2-2as Suppression Contributes to the Pathogenesis of Sonic Hedgehog Medulloblastoma
Nkx2-2as Suppression Contributes to the Pathogenesis of Sonic Hedgehog Medulloblastoma
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Nkx2-2as 抑制有助于 Sonic Hedgehog 髓母细胞瘤的发病机制
DOI：
10.1158/0008-5472.can-17-1631
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发表时间：
2018
期刊：
影响因子：
11.2
通讯作者：
Jia Lintao
中科院分区：
文献类型：
--
作者：
Zhang Yimeng;Wang Ting;Wang Shan;Xiong Yanlu;Zhang Rui;Zhang Xiang;Zhao Jing;Yang An-Gang;Wang Lei;Jia Lintao
异常的Hedgehog信号传导和Gli家族转录激活因子的过度激活是髓母细胞瘤（MB）（最常见的人类儿科脑恶性肿瘤）的关键驱动因素。MB主要来源于小脑颗粒神经元祖细胞（CGNP），但CGNP转化的机制仍不清楚。在这项研究中，我们发现，抑制非编码RNA Nkx 2 -2as促进Sonic Hedgehog（Shh）增强MB的发展。Nkx 2 -2as作为与miR-103和miR-107竞争的内源性RNA发挥作用，将它们隔离，从而解除其肿瘤抑制靶点BTG 2和LATS 1的抑制，并阻碍细胞分裂和迁移。我们还发现Nkx 2 -2as束缚miR-548 m并废除其LATS 2靶向活性。Shh信号通过上调转录抑制因子FoxD 1损害Nkx 2 -2as表达。在Shh亚群MB的临床标本中，我们验证了上述蛋白质的协调表达。值得注意的是，Nkx 2 -2as的外源性表达抑制肿瘤发生并延长MB小鼠模型中的动物存活。我们的研究结果阐明了非编码RNA在Hedgehog信号传导和MB发生中的作用，这对确定MB治疗的候选治疗靶点具有意义。意义：这些研究结果阐明了非编码RNA在Hedgehog信号传导中的作用以及Hedgehog和Hippo通路之间的相互作用在髓母细胞瘤发病机制中。Cancer Res; 78（4）; 962-73。©2017 AACR.
Aberrant Hedgehog signaling and excessive activation of the Gli family of transcriptional activators are key drivers of medulloblastoma (MB), the most common human pediatric brain malignancy. MB originates mainly from cerebellar granule neuron progenitors (CGNP), but the mechanisms underlying CGNP transformation remain largely obscure. In this study, we found that suppression of the noncoding RNA Nkx2-2as promoted Sonic Hedgehog (Shh)-potentiated MB development. Nkx2-2as functioned as a competing endogenous RNA against miR-103 and miR-107, sequestering them and thereby derepressing their tumor suppressive targets BTG2 and LATS1 and impeding cell division and migration. We also found that Nkx2-2as tethered miR-548m and abrogated its LATS2 targeting activity. Shh signaling impaired Nkx2-2as expression by upregulating the transcriptional repressor FoxD1. In clinical specimens of Shh-subgroup MB, we validated coordinated expression of the aforementioned proteins. Notably, exogenous expression of Nkx2-2as suppressed tumorigenesis and prolonged animal survival in MB mouse models. Our findings illuminate the role of noncoding RNAs in Hedgehog signaling and MB occurrence, with implications for identifying candidate therapeutic targets for MB treatment.Significance:These findings illuminate the role of noncoding RNAs in Hedgehog signaling and an interplay between the Hedgehog and Hippo pathways in medulloblastoma pathogenesis.Cancer Res; 78(4); 962–73. ©2017 AACR.