microRNA-558 facilitates the expression of hypoxia-inducible factor 2 alpha through binding to 5'-untranslated region in neuroblastoma.
microRNA-558 facilitates the expression of hypoxia-inducible factor 2 alpha through binding to 5'-untranslated region in neuroblastoma.
复制标题
DOI：
10.18632/oncotarget.9813
复制
发表时间：
2016-06-28
期刊：
影响因子：
--
通讯作者：
Tong Q
中科院分区：
文献类型：
--
作者：
Qu H;Zheng L;Song H;Jiao W;Li D;Fang E;Wang X;Mei H;Pu J;Huang K;Tong Q
神经母细胞瘤(NB)是儿童最常见的颅外实体瘤。我们以前的研究表明，低氧诱导因子2α(HIF-2α)是bHLHPAS转录因子家族的成员之一，在非低氧条件下促进NB的进展。然而，神经母细胞瘤中缺氧诱导因子-2α表达的机制仍然很大程度上仍不清楚。在这里，通过对计算算法程序的分析，我们确定microRNA-558(miR-558)是NB中HIF-2α表达的重要调节因子。我们证明，miR558通过招募ArgAerte2(AGO2)在翻译水平上促进了NB细胞中HIF-2α的表达。在机制上，miR-558直接与其5‘-非翻译区的互补位点结合，促进AGO2与真核翻译起始因子4E(EIF4E)结合蛋白1的结合，从而增加eIF4E的丰度和HIF-2的α翻译。此外，miR-558在体内外促进了NB细胞的生长、侵袭、转移和血管生成，这些生物学特性可通过下调AGO2、eIF4E或HIF-2α而被挽救。临床标本中miR-558、AGO2和eIF4E均高表达，且与HIF-2α表达呈正相关。MiR-558、HIF-2α、AGO2或eIF4E水平高的患者生存概率较低。综上所述，这些结果表明，miR-558通过与其5‘端非编码区结合，促进了HIF-2α的表达，从而促进了NB的发生和侵袭性。
Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Our previous studies have shown that hypoxia-inducible factor 2 alpha (HIF-2α), one member of the bHLH-PAS transcription factor family, facilitates the progression of NB under non-hypoxic conditions. However, the mechanisms underlying HIF-2α expression in NB still remain largely unknown. Herein, through analyzing the computational algorithm programs, we identified microRNA-558 (miR-558) as a crucial regulator of HIF-2α expression in NB. We demonstrated that miR-558 promoted the expression of HIF-2α at translational levels in NB cells through recruiting Argonaute 2 (AGO2). Mechanistically, miR-558 directly bound with its complementary site within 5′-untranslated region (5′-UTR) to facilitate the binding of AGO2 to eukaryotic translation initiation factor 4E (eIF4E) binding protein 1, resulting in increased eIF4E enrichment and HIF-2α translation. In addition, miR-558 promoted the growth, invasion, metastasis, and angiogenesis of NB cells in vitro and in vivo, and these biological features were rescued by knockdown of AGO2, eIF4E, or HIF-2α. In clinical NB specimens, miR-558, AGO2, and eIF4E were highly expressed and positively correlated with HIF-2α expression. Patients with high miR-558, HIF-2α, AGO2, or eIF4E levels had lower survival probability. Taken together, these results demonstrate that miR-558 facilitates the expression of HIF-2α through bindingto its 5′-UTR, thus promoting the tumorigenesis and aggressiveness of NB.
登录
查看更多内容
靶向转录起始位点的小 RNA 通过干扰人类癌细胞中的转录起始来诱导乙酰肝素酶沉默
影响因子：
3.7
作者：
Jiang G;Zheng L;Pu J;Mei H;Zhao J;Huang K;Zeng F;Tong Q
通讯作者：
Tong Q
Intelectin 1 通过上调 N-myc 下游调节基因 2 来抑制神经母细胞瘤细胞的生长、侵袭和转移。
影响因子：
37.3
作者：
Li D;Mei H;Pu J;Xiang X;Zhao X;Qu H;Huang K;Zheng L;Tong Q
通讯作者：
Tong Q
捕获microRNA结合的mRNA将肿瘤抑制器miR-34a识别为生长因子信号传导的调节剂。
影响因子：
4.5
作者：
Lal A;Thomas MP;Altschuler G;Navarro F;O'Day E;Li XL;Concepcion C;Han YC;Thiery J;Rajani DK;Deutsch A;Hofmann O;Ventura A;Hide W;Lieberman J
通讯作者：
Lieberman J
影响因子：
4.8
作者：
Lima, Walt F.;Wu, Hongjiang;Crooke, Stanley T.
通讯作者：
Crooke, Stanley T.
影响因子：
7
作者：
Lee, Inhan;Ajay, Subramanian S.;Athey, Brian D.
通讯作者：
Athey, Brian D.