Oncotarget

Research Papers:

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

Hongxia Qu _, Liduan Zheng, Huajie Song, Wanju Jiao, Dan Li, Erhu Fang, Xiaojing Wang, Hong Mei, Jiarui Pu, Kai Huang and Qiangsong Tong

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Oncotarget. 2016; 7:40657-40673. https://doi.org/10.18632/oncotarget.9813

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Abstract

Hongxia Qu1,*, Liduan Zheng2,3,*, Huajie Song1, Wanju Jiao2, Dan Li1, Erhu Fang1, Xiaojing Wang1, Hong Mei1, Jiarui Pu1, Kai Huang3, Qiangsong Tong1,3

1Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, P. R. China

2Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, P. R. China

3Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, P. R. China

*These authors have contributed equally to this work

Correspondence to:

Qiangsong Tong, email: qs_tong@hotmail.com

Keywords: neuroblastoma, microRNA-558, hypoxia-inducible factor 2 alpha, Argonaute 2, eukaryotic translation initiation factor 4E

Received: February 12, 2016    Accepted: May 20, 2016    Published: June 3, 2016

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.


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