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MYCN-regulated miRNA-92 inhibits secretion of the tumor suppressor DICKKOPF-3 (DKK3) in neuroblastoma.

Journal article
Authors Bjørn Helge Haug
Jørn R Henriksen
Jochen Buechner
Dirk Geerts
Ellen Tømte
Per Kogner
Tommy Martinsson
Trond Flægstad
Baldur Sveinbjørnsson
Christer Einvik
Published in Carcinogenesis
Volume 32
Issue 7
Pages 1005-12
ISSN 1460-2180
Publication year 2011
Published at Institute of Biomedicine, Department of Medical and Clinical Genetics
Pages 1005-12
Language en
Links dx.doi.org/10.1093/carcin/bgr073
Keywords 3' Untranslated Regions, Blood Vessels, metabolism, Cell Line, Tumor, DNA Methylation, Gene Knockdown Techniques, Genes, Tumor Suppressor, Humans, Immunohistochemistry, Intercellular Signaling Peptides and Proteins, genetics, metabolism, MicroRNAs, genetics, physiology, Neuroblastoma, blood supply, metabolism, pathology, Nuclear Proteins, genetics, physiology, Oncogene Proteins, genetics, physiology, Oncogenes, Polymerase Chain Reaction, Promoter Regions, Genetic, Reverse Transcriptase Polymerase Chain Reaction
Subject categories Medical Genetics

Abstract

The MYCN oncogene is frequently amplified in neuroblastoma. It is one of the most consistent markers of bad prognosis for this disease. Dickkopf-3 (DKK3) is a secreted protein of the DKK family of Wnt regulators. It functions as a tumor suppressor in a range of cancers, including neuroblastoma. MYCN was recently found to downregulate DKK3 mRNA. In this study, we show that MYCN knockdown in MYCN-amplified (MNA) neuroblastoma cell lines increases secretion of endogenous DKK3 to the culture media. MicroRNAs (miRNAs) are ∼20 nt long single-stranded RNA molecules that downregulate messenger RNAs by targeting the 3' untranslated region (3'UTR). Many miRNAs regulate genes involved in the pathogenesis of cancer and are extensively deregulated in different tumors. Using miRNA target prediction software, we found several MYCN-regulated miRNAs that could target the 3'UTR sequence of DKK3, including mir-92a, mir-92b and let-7e. Luciferase expression from a reporter vector containing the DKK3-3'UTR was decreased when this construct was cotransfected with mir-92a, mir-92b or let-7e in HEK293 cells. Mutation of the mir-92 seed sequence in the 3'UTR completely rescued the observed decrease in reporter expression when cotransfected with mir-92a and mir-92b. Antagomir and miRNA-mimic transfections in neuroblastoma cell lines confirmed that DKK3 secretion to the culture media is regulated by mir-92. Consistent with reports from other cancers, we found DKK3 to be expressed in the endothelium of primary neuroblastoma samples and to be absent in tumors with MYCN amplification. Our data demonstrate that MYCN-regulated miRNAs are able to modulate the expression of the tumor suppressor DKK3 in neuroblastoma.

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