title: miR-542-3p exerts tumor suppressive functions in neuroblastoma by downregulating Survivin.
abstract: MicroRNAs (miRNAs) are deregulated in a variety of human cancers, including neuroblastoma, the most common extracranial tumor of childhood. We previously reported a signature of 42 miRNAs to be highly predictive of neuroblastoma outcome. One miRNA in this signature, miR-542, was downregulated in tumors from patients with adverse outcome. Reanalysis of quantitative PCR and next-generation sequencing transcript data revealed that miR-542-5p as well as miR-542-3p expression is inversely correlated with poor prognosis in neuroblastoma patients. We, therefore, analyzed the function of miR-542 in neuroblastoma tumor biology. Ectopic expression of miR-542-3p in neuroblastoma cell lines reduced cell viability and proliferation, induced apoptosis and downregulated Survivin. Survivin expression was also inversely correlated with miR-542-3p expression in primary neuroblastomas. Reporter assays confirmed that miR-542-3p directly targeted Survivin. Downregulating Survivin using siRNA copied the phenotype of miR-542-3p expression in neuroblastoma cell lines, while cDNA-mediated ectopic expression of Survivin partially rescued the phenotype induced by miR-542-3p expression. Treating nude mice bearing neuroblastoma xenografts with miR-542-3p-loaded nanoparticles repressed Survivin expression, decreased cell proliferation and induced apoptosis in the respective xenograft tumors. We conclude that miR-542-3p exerts its tumor suppressive function in neuroblastoma, at least in part, by targeting Survivin. Expression of miR-542-3p could be a promising therapeutic strategy for treating aggressive neuroblastoma.
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany; German Cancer Consortium (DKTK), Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Althoff
authors.forename: Sven
authors.initials: S
authors.lastname: Lindner
authors.forename: Andrea
authors.initials: A
authors.lastname: Odersky
authors.forename: Pieter
authors.initials: P
authors.lastname: Mestdagh
authors.forename: Anneleen
authors.initials: A
authors.lastname: Beckers
authors.forename: Sarah
authors.initials: S
authors.lastname: Karczewski
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Molenaar
authors.forename: Anna
authors.initials: A
authors.lastname: Bohrer
authors.forename: Shirley
authors.initials: S
authors.lastname: Knauer
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.forename: Matthias
authors.initials: M
authors.lastname: Epple
authors.forename: Diana
authors.initials: D
authors.lastname: Kozlova
authors.forename: Sena
authors.initials: S
authors.lastname: Yoon
authors.forename: Kwanghee
authors.initials: K
authors.lastname: Baek
authors.forename: Jo
authors.initials: J
authors.lastname: Vandesompele
authors.forename: Angelika
authors.initials: A
authors.lastname: Eggert
authors.forename: Alexander
authors.initials: A
authors.lastname: Schramm
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Schulte
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015536:Down-Regulation; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D000071447:N-Myc Proto-Oncogene Protein; D053758:Nanoparticles; D009447:Neuroblastoma / Q000473:pathology* / Q000517:prevention & control; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; C572357:MIRN542 microRNA, human; C459801:MYCN protein, human; D035683:MicroRNAs; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D000077022:Survivin
keywords: Survivin; miR-542-3p; nanoparticles; neuroblastoma