microRNA-558 facilitates the expression of hypoxia-inducible factor 2 alpha through binding to 5'-untranslated region in neuroblastoma

• Published in: Oncotarget Vol. 7; no. 26; pp. 40657 - 40673
• Main Authors: Qu, Hongxia, Zheng, Liduan, Song, Huajie, Jiao, Wanju, Li, Dan, Fang, Erhu, Wang, Xiaojing, Mei, Hong, Pu, Jiarui, Huang, Kai, Tong, Qiangsong
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 28.06.2016
• Subjects: 5' Untranslated Regions; Algorithms; Animals; Argonaute Proteins - metabolism; Basic Helix-Loop-Helix Transcription Factors - metabolism; Brain Neoplasms - metabolism; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs - genetics; MicroRNAs - metabolism; Neoplasm Invasiveness; Neovascularization, Pathologic; Neuroblastoma - metabolism; Nucleocytoplasmic Transport Proteins - metabolism; Research Paper; neuroblastoma; microRNA-558; eukaryotic translation initiation factor 4E; hypoxia-inducible factor 2 alpha; Argonaute 2
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.9813

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.