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

Abstract

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.

Improving Bioinformatics Prediction of microRNA Targets by Ranks Aggregation

“…associated computation times, but our approach is generalizable to miRNAs of all origins. Although there is so far a high prevalence of miRNA interaction sites found in the 3'UTR, recent papers have shown that some miRNAs can also regulate mRNAs by binding with the 5'UTR and CDS region of their targets (Moretti et al, 2010;Qu et al, 2016). Even though the value of these sites is not yet clearly established in the literature, this information remains important to get an integrated view of the predicted miRNA interaction sites on the mRNA.…”

miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target

“…Although no miRNA has been proposed to directly target HIF-2 levels in human endothelium to date, recent work indicates that miR-588 in neuroblastoma stimulates HIF-2α expression through interaction with 5′ UTR of EPAS1 mRNA [ 139 ]. miR-558 directly binds with its complementary site within this 5′-UTR and facilitates the binding of AGO2 to the eukaryotic translation initiation factor 4E (eIF4E) binding protein 1 and results in increased eIF4E enrichment and HIF-2α translation [ 139 ]. Furthermore, miR-17, and miR-18b have been postulated to directly reduce EPAS1 in human macrophages [ 140 ].…”

Hypoxia and hypoxia-inducible factors in neuroblastoma

“…Few studies have investigated the impact of microRNA-regulated expression of HIF-2α in neuroblastoma but, interestingly, in relation to the 5′-cap-dependent translation described above, Qu et al identified miR-558 as a crucial regulator of HIF-2α (Qu et al 2016 ). Mechanistically, miR-558 binds directly to the 5′-UTR of HIF-2α to facilitate binding between Argonaute 2 (AGO2) and eIF4E, actively promoting HIF-2α translation.…”