Hypoxic Glioma Stem Cell-Derived Exosomes Containing Linc01060 Promote Progression of Glioma by Regulating the MZE1/c-Myc/HIF1α Axis
Hypoxic Glioma Stem Cell-Derived Exosomes Containing Linc01060 Promote Progression of Glioma by Regulating the MZE1/c-Myc/HIF1α Axis
复制标题
含有 Linc01060 的缺氧胶质瘤干细胞衍生的外泌体通过调节 MZF1/c-Myc/HIF-1α 轴促进胶质瘤的进展
DOI：
10.1158/0008-5472.can-20-2270
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发表时间：
2021-01-01
期刊：
影响因子：
11.2
通讯作者：
Xiong, Nanxiang
中科院分区：
文献类型：
--
作者：
Li, Junjun;Liao, Tingting;Xiong, Nanxiang
胶质瘤干细胞（GSC）是胶质瘤中具有特殊增殖和分化能力的肿瘤细胞亚群。它们是肿瘤复发的主要原因之一，特别是在缺氧条件下。尽管已知长链非编码RNA（lncRNA）参与许多生物学过程并暗示与某些疾病的发生有关，但它们在肿瘤发生和进展中的作用仍然知之甚少。在这里，我们探讨了来源于缺氧GSC（H-GSC）的lncRNA导致胶质瘤进展的机制。分离和鉴定Linc 01060基因、含有它们的外泌体以及来自调节该基因的肿瘤细胞的蛋白质，允许研究Linc 01060对增殖和糖代谢的影响。H-GSC通过将外泌体转移到胶质瘤细胞中发挥作用，导致Linc 01060水平显著增加。在机制上，Linc 01060直接与转录因子髓样锌指1（MZF 1）相互作用并增强其稳定性。Linc 01060促进MZE 1的核转位，并促进MZE 1介导的c-Myc转录活性。此外，c-Myc在转录后水平增强缺氧诱导因子-1 α（HIF 1 α）的积累。HIF 1 α结合Linc 01060启动子的激素反应元件，上调Linc 01060基因的转录。临床上，Linc 01060在胶质瘤中表达上调，且与肿瘤分级和不良临床预后显著相关。总体而言，这些数据表明，从H-GSCs分泌的含Linc 01060的外泌体激活了胶质瘤细胞中的原癌信号通路，从而促进疾病进展。意义：这些发现表明，抑制含Linc 01060的外泌体或靶向Linc 01060/MZEI/c-Myc/HIF 1 α轴可能是胶质瘤的有效治疗策略。
Glioma stem cells (GSC) are a subpopulation of tumor cells with special abilities to proliferate and differentiate in gliomas. They are one of the main causes of tumor recurrence, especially under hypoxic conditions. Although long noncoding RNAs (lncRNA) are known to he involved in numerous biological processes and are implied in the occurrence of certain diseases, their role in tumor development and progression remains poorly understood. Here we explored the mechanisms by which lncRNA derived from hypoxic GSCs (H-GSC) cause glioma progression. Isolation and identification of the Linc01060 gene, the exosomes containing them, and the proteins from tumor cells regulating the gene allowed for studying the effects of Linc01060 on proliferation and glycometabolism. H-GSC exerted their effects by transferring exosomes to glioma cells, resulting in a significant increase in Linc01060 levels. Mechanistically, Linc01060 directly interacted with the transcription factor myeloid zinc finger 1 (MZF1) and enhanced its stability. Linc01060 facilitated nuclear translocation of MZE1 and promoted MZE1-mediated c-Myc transcriptional activities. In addition, c-Myc enhanced the accumulation of the hypoxia-inducible factor-1 alpha (HIF1 alpha) at the posttranscriptional level. HIF1 alpha bound the hormone response elements of the Linc01060 promoter, upregulating the transcription of Linc01060 gene. Clinically, Linc01060 was upregulated in glioma and was significantly correlated with tumor grade and poor clinical prognosis. Overall, these data show that secretion of Linc01060-containing exosomes from H-GSCs activates prooncogenic signaling pathways in glioma cells to promote disease progression.Significance: These findings suggest that inhibition of Linc01060-containing exosomes or targeting the Linc01060/MZEI/c-Myc/HIF1 alpha axis may be an effective therapeutic strategy in glioma.