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Cancer Lett. 2015 Sep 28;366(1):123-32. doi: 10.1016/j.canlet.2015.06.015. Epub 2015 Jun 26.

MYCN-driven regulatory mechanisms controlling LIN28B in neuroblastoma.

Author information

1
Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium.
2
Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, PO Box 81, Randwick, NSW 2031, Australia.
3
Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
4
Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany; Institute of Pharmacy and Molecular Biotechnology, and Bioquant Center, University of Heidelberg, Im Neuenheimer Feld 267, Heidelberg 69120, Germany.
5
Division of Pediatric Hematology-Oncology and Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, 1102 Bates Street, Houston, TX 77030, USA.
6
Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium; Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
7
Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany; German Consortium for Translational Cancer Research (DKTK), Partner Site Essen/Duesseldorf, Essen, Germany.
8
Department of Oncogenomics, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
9
Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany; Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany; German Consortium for Translational Cancer Research (DKTK), Partner Site Essen/Duesseldorf, Essen, Germany; Translational Neuro-Oncology, West German Cancer Center (WTZ), University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; Centre for Medical Biotechnology, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany.
10
Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
11
Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: franki.speleman@ugent.be.

Abstract

LIN28B has been identified as an oncogene in various tumor entities, including neuroblastoma, a childhood cancer that originates from neural crest-derived cells, and is characterized by amplification of the MYCN oncogene. Recently, elevated LIN28B expression levels were shown to contribute to neuroblastoma tumorigenesis via let-7 dependent de-repression of MYCN. However, additional insight in the regulation of LIN28B in neuroblastoma is lacking. Therefore, we have performed a comprehensive analysis of the regulation of LIN28B in neuroblastoma, with a specific focus on the contribution of miRNAs. We show that MYCN regulates LIN28B expression in neuroblastoma tumors via two distinct parallel mechanisms. First, through an unbiased LIN28B-3'UTR reporter screen, we found that miR-26a-5p and miR-26b-5p regulate LIN28B expression. Next, we demonstrated that MYCN indirectly affects the expression of miR-26a-5p, and hence regulates LIN28B, therefore establishing an MYCN-miR-26a-5p-LIN28B regulatory axis. Second, we provide evidence that MYCN regulates LIN28B expression via interaction with the LIN28B promoter, establishing a direct MYCN-LIN28B regulatory axis. We believe that these findings mark LIN28B as an important effector of the MYCN oncogenic phenotype and underline the importance of MYCN-regulated miRNAs in establishing the MYCN-driven oncogenic process.

KEYWORDS:

Cross-species; Integrative analysis; MicroRNA

PMID:
26123663
PMCID:
PMC4837470
DOI:
10.1016/j.canlet.2015.06.015
[Indexed for MEDLINE]
Free PMC Article

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