microRNA-558 facilitates the expression of hypoxia-inducible factor 2 alpha through binding to 5'-untranslated region in neuroblastoma.
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.
Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, P. R. China.
Hongxia
H
Qu
Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, P. R. China.|Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, P. R. China.
Liduan
L
Zheng
Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, P. R. China.
Huajie
H
Song
Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, P. R. China.
Wanju
W
Jiao
Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, P. R. China.
Dan
D
Li
Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, P. R. China.
Erhu
E
Fang
Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, P. R. China.
Xiaojing
X
Wang
Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, P. R. China.
Hong
H
Mei
Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, P. R. China.
Jiarui
J
Pu
Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, P. R. China.
Kai
K
Huang
Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, P. R. China.|Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, P. R. China.
Qiangsong
Q
Tong
D020121:5' Untranslated Regions; D000465:Algorithms; D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D009447:Neuroblastoma / Q000378:metabolism*; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D020121:5' Untranslated Regions; D060565:Argonaute Proteins; D051792:Basic Helix-Loop-Helix Proteins; D035683:MicroRNAs; D029543:Nucleocytoplasmic Transport Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C466422:AGO2 protein, human; C411571:EIF4ENIF1 protein, human; C000603689:MIRN-558 microRNA, human
Argonaute 2; eukaryotic translation initiation factor 4E; hypoxia-inducible factor 2 alpha; microRNA-558; neuroblastoma