title: Regulation of Nuclear Hormone Receptors by MYCN-Driven miRNAs Impacts Neural Differentiation and Survival in Neuroblastoma Patients.
abstract: MYCN amplification and MYC signaling are associated with high-risk neuroblastoma with poor prognosis. Treating these tumors remains challenging, although therapeutic approaches stimulating differentiation have generated considerable interest. We have previously shown that the MYCN-regulated miR-17∼92 cluster inhibits neuroblastoma differentiation by repressing estrogen receptor alpha. Here, we demonstrate that this microRNA (miRNA) cluster selectively targets several members of the nuclear hormone receptor (NHR) superfamily, and we present a unique NHR signature associated with the survival of neuroblastoma patients. We found that suppressing glucocorticoid receptor (GR) expression in MYCN-driven patient and mouse tumors was associated with an undifferentiated phenotype and decreased survival. Importantly, MYCN inhibition and subsequent reactivation of GR signaling promotes neural differentiation and reduces tumor burden. Our findings reveal a key role for the miR-17∼92-regulated NHRs in neuroblastoma biology, thereby providing a potential differentiation approach for treating neuroblastoma patients.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden. Electronic address: diogo.ribeiro@ki.se.
authors.forename: Diogo
authors.initials: D
authors.lastname: Ribeiro
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Marcus D R
authors.initials: MDR
authors.lastname: Klarqvist
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Ulrica K
authors.initials: UK
authors.lastname: Westermark
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Ganna
authors.initials: G
authors.lastname: Oliynyk
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Johanna
authors.initials: J
authors.lastname: Dzieran
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Kock
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Carolina
authors.initials: C
authors.lastname: Savatier Banares
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital and Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Hertwig
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: John Inge
authors.initials: JI
authors.lastname: Johnsen
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital and Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Kogner
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Jakob
authors.initials: J
authors.lastname: Lovén
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden. Electronic address: marie.arsenian.henriksson@ki.se.
authors.forename: Marie
authors.initials: M
authors.lastname: Arsenian Henriksson
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D035683:MicroRNAs; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid
keywords: MYC inhibitor; MYCN; cancer therapy; differentiation; glucocorticoid receptor; miR-17∼92; miRNAs; neuroblastoma; nuclear hormone receptors