Mineo Marco, Ricklefs Franz, Rooj Arun K, Lyons Shawn M, Ivanov Pavel, Ansari Khairul I, Nakano Ichiro, Chiocca E Antonio, Godlewski Jakub, Bronisz Agnieszka
Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
Cell Rep. 2016 Jun 14;15(11):2500-9. doi: 10.1016/j.celrep.2016.05.018. Epub 2016 Jun 2.
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, upregulated in mesenchymal GSCs. Its deregulation affects GSC growth, self-renewal, and hypoxia-dependent molecular reprogramming. Among 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. Downregulation 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 and targets and indirectly by modulating responses to hypoxic stress depending on the subtype-specific genetic context.
长链非编码RNA（lncRNA）在多形性胶质母细胞瘤（GBM）的病理生物学中作用尚不明确。这些肿瘤在基因和表型上具有异质性，存在转录组亚型特异性的GBM干细胞样细胞（GSC），它们能够适应脑肿瘤微环境，包括低氧微环境。我们将缺氧诱导因子1α反义RNA 2（HIF1A-AS2）鉴定为一种亚型特异性的缺氧诱导lncRNA，在间充质GSC中上调。其失调会影响GSC的生长、自我更新以及缺氧依赖性分子重编程。在HIF1A-AS2相互作用组中，IGF2BP2和DHX9被鉴定为直接相互作用伙伴。这种关联对于维持其靶基因HMGA1的表达是必需的。HIF1A-AS2的下调导致间充质GSC肿瘤生长延迟、生存获益，并在体内损害HMGA1的表达。我们的数据表明，HIF1A-AS2通过其相互作用组和靶标直接发挥作用，并通过根据亚型特异性遗传背景调节对缺氧应激的反应间接促进GSC在肿瘤微环境中的分化和对缺氧的适应。
