Regulation of Nuclear Hormone Receptors by MYCN-Driven miRNAs Impacts Neural Differentiation and Survival in Neuroblastoma Patients
Diogo Ribeiro,
Marcus D.R. Klarqvist,
Ulrica K. Westermark,
Ganna Oliynyk,
Johanna Dzieran,
Anna Kock,
Carolina Savatier Banares,
Falk Hertwig,
John Inge Johnsen,
Matthias Fischer,
Per Kogner,
Jakob Lovén,
Marie Arsenian Henriksson
Affiliations
Diogo Ribeiro
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden
Marcus D.R. Klarqvist
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden
Ulrica K. Westermark
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden
Ganna Oliynyk
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden
Johanna Dzieran
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden
Anna Kock
Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, 171 76 Stockholm, Sweden
Carolina Savatier Banares
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden
Falk Hertwig
Department of Pediatric Oncology and Hematology, University Children’s Hospital and Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
John Inge Johnsen
Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, 171 76 Stockholm, Sweden
Matthias Fischer
Department of Pediatric Oncology and Hematology, University Children’s Hospital and Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
Per Kogner
Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, 171 76 Stockholm, Sweden
Jakob Lovén
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden
Marie Arsenian Henriksson
Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, 171 77 Stockholm, Sweden
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.
