The Long Non-coding RNA HIF1A-AS2 Facilitates the Maintenance of Mesenchymal Glioblastoma Stem-like Cells in Hypoxic Niches.
The Long Non-coding RNA HIF1A-AS2 Facilitates the Maintenance of Mesenchymal Glioblastoma Stem-like Cells in Hypoxic Niches.
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DOI：
10.1016/j.celrep.2016.05.018
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发表时间：
2016-06-14
期刊：
影响因子：
8.8
通讯作者：
Bronisz A
中科院分区：
文献类型：
--
作者：
Mineo M;Ricklefs F;Rooj AK;Lyons SM;Ivanov P;Ansari KI;Nakano I;Chiocca EA;Godlewski J;Bronisz A
长非编码RNA(LncRNAs)在多形性胶质母细胞瘤(GBM)的病理生物学中具有未知的作用。这些肿瘤在基因和表型上是异质性的，具有转录组亚型特异性的GBM干细胞(GSCs)，它们适应脑肿瘤的微环境，包括缺氧的壁龛。我们发现低氧诱导因子1α-反义RNA 2(HIF1a-AS2)是一种亚型特异性的低氧诱导的lncRNA，在间充质干细胞中上调表达。它的去调控影响了GSC的生长、自我更新和低氧依赖的分子重编程。在HIF1a-AS2相互作用组中，IGF2BP2和DHX9被确定为直接合作伙伴。这种关联是维持其目标基因HMGA1表达所必需的。HIF1a-AS2的下调导致间叶性GSC肿瘤生长延迟，生存受益，体内HMGA1表达受损。我们的数据表明，HIF1a-AS2有助于GSCs在肿瘤微环境中的物种形成和对低氧的适应，直接通过其相互作用组/靶点发挥作用，并根据亚型特定的遗传背景间接调节对低氧应激的反应。
Long-non-coding RNAs (lncRNAs) have an undefined role in the pathobiology of glioblastoma multiforme (GBM). These tumors are genetically and phenotypically heterogeneous with transcriptome subtype-specific GBM stem-like cells (GSCs) that adapt to the brain tumor microenvironment, including hypoxic niches. We identified hypoxia inducible factor 1 alpha-antisense RNA 2 (HIF1A-AS2) as a subtype-specific hypoxia inducible lncRNA, up-regulated in mesenchymal GSCs. Its deregulation affects GSC growth, self-renewal and hypoxia-dependent molecular reprogramming. Amongst the HIF1A-AS2 interactome, IGF2BP2 and DHX9 were identified as direct partners. This association was needed for maintenance of expression of their target gene, HMGA1. Down-regulation of HIF1A-AS2 led to delayed growth of mesenchymal GSC tumors, survival benefits, and impaired expression of HMGA1 in vivo. Our data demonstrate that HIF1A-AS2 contributes to GSCs’ speciation and adaptation to hypoxia within the tumor microenvironment, acting directly through its interactome/targets and indirectly by modulating responses to hypoxic stress depending on the subtype-specific genetic context.