title: microRNA-221 Enhances MYCN via Targeting Nemo-like Kinase and Functions as an Oncogene Related to Poor Prognosis in Neuroblastoma.
abstract: Purpose:MYCNis one of the most well-characterized genetic markers of neuroblastoma. However, the mechanisms as to howMYCNmediate neuroblastoma tumorigenesis are not fully clear. Increasing evidence has confirmed that the dysregulation of miRNAs is involved in MYCN-mediated neuroblastoma tumorigenesis, supporting their potential as therapeutic targets for neuroblastoma. Although miR-221 has been reported as one of the upregulated miRNAs, the interplay between miR-221 and MYCN-mediated neuroblastoma progression remains largely elusive.Experimental Design:The expression of miR-221 in the formalin-fixed, paraffin-embedded tissues from 31 confirmed patients with neuroblastoma was detected by locked nucleic acid-in situhybridization and qRT-PCR. The correlation between miR-221 expression and clinical features in patients with neuroblastoma was assessed. The mechanisms as to how miR-221 regulate MYCN in neuroblastoma were addressed. The effect of miR-221 on cellular proliferation in neuroblastoma was determined bothin vitroandin vivoResults:miR-221 was significantly upregulated in neuroblastoma tumor cells and tissues that overexpress MYCN, and high expression of miR-221 was positively associated with poor survival in patients with neuroblastoma. Nemo-like kinase (NLK) as a direct target of miR-221 in neuroblastoma was verified. In addition, overexpression of miR-221 decreased LEF1 phosphorylation but increased the expression of MYCN via targeting of NLK and further regulated cell cycle, particularly in S-phase, promoting the growth of neuroblastoma cells.Conclusions:This study provides a novel insight for miR-221 in the control of neuroblastoma cell proliferation and tumorigenesis, suggesting potentials of miR-221 as a prognosis marker and therapeutic target for patients with MYCN overexpressing neuroblastoma.Clin Cancer Res; 23(11); 2905-18. ©2016 AACR.
authors.affiliation: Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: He
authors.affiliation: Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China.
authors.forename: Zheng-Lan
authors.initials: ZL
authors.lastname: Tan
authors.affiliation: Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Mou
authors.affiliation: Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China.
authors.forename: Fang-Jie
authors.initials: FJ
authors.lastname: Liu
authors.affiliation: Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Liu
authors.affiliation: Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China.
authors.forename: Chao-Wen
authors.initials: CW
authors.lastname: Yu
authors.affiliation: Department of Pathology, Chongqing Medical University, Chongqing, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Oncological Surgery, Children's Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Lin-Ya
authors.initials: LY
authors.lastname: Lv
authors.affiliation: Department of Oncological Surgery, Children's Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Oncological Surgery, Children's Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China.|Department of Pathology and Laboratory Medicine, Geisel School of Medicine Dartmouth College, Lebanon, New Hampshire.
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Bao
authors.affiliation: Department of Health Statistics, School of Public Health, Chongqing Medical University, Chongqing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Peng
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Center for Clinical Molecular Medicine, Children's Hospital, Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China. zoulin74@126.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Zou
mesh_terms: D014408:Biomarkers, Tumor; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D058990:Molecular Targeted Therapy; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics*; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; D000071447:N-Myc Proto-Oncogene Protein; D017346:Protein Serine-Threonine Kinases; C525709:MIR221, human; C459801:MYCN protein, human; C470551:NLK protein, human