Mini-review MicroRNAs in the pathogenesis of neuroblastoma Johannes H. Schulte a, * , Sebastian Horn b,d , Stefanie Schlierf a , Alexander Schramm a , Lukas C. Heukamp c , Holger Christiansen d , Reinhard Buettner c , Bernd Berwanger d , Angelika Eggert a a Department of Pediatric Oncology and Haematology, University Children’s Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany b Institute of Molecular Biology and Tumor Research (IMT), Philipps University of Marburg, Emil-Mannkopff-Strasse 2, 35037 Marburg, Germany c Institute of Pathology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany d Children’s Hospital Medical Centre, University Hospital Giessen and Marburg, Baldinger Strasse, 35043 Marburg, Germany article info Article history: Received 19 April 2008 Received in revised form 19 May 2008 Accepted 2 June 2008 Keywords: Neuroblastoma miRNA MicroRNA miR-34a miR-17-92 Expression profiling abstract MicroRNAs constitute a family of small RNA species that regulate translation and stability of mRNA. This additional layer of epigenetic regulation has escaped discovery until recently, and introduces another level between mRNA expression profiling and proteomics. Since microRNAs are involved in regulating most, if not all cellular processes, their involve- ment in oncogenesis was anticipated. Indeed, soon after their discovery, microRNAs were found to act as tumor suppressor genes by blocking the translation of oncogenes and act as oncogenes by inhibiting the translation of tumor suppressor genes. Here we review the most recent attempts aiming to analyze the functional roles of microRNAs in neuroblas- toma, the most devastating solid tumor in childhood. Ó 2008 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Neuroblastoma is the most common solid extracranial malignancy of childhood, accounting for approximately 15% of all childhood cancer deaths. Tumor cells arise from neural crest progenitor cells that fail to differentiate along their predefined route. The clinical course of neuro- blastoma is extremely heterogeneous, spanning tumors with favorable biological features capable of spontaneous regression or differentiation into benign derivates with- out therapy to tumors with unfavorable biology that fatally progress despite multimodal aggressive therapy. The concert of biological factors constituting favorable or unfavorable biology is complex. Young patient age as well as high expression of the TrkA neurotrophin recep- tor and structural chromosomal stability in the tumor are features of good prognostic neuroblastoma. In con- trast, high expression of the TrkB neurotrophin receptor, amplification of the MYCN oncogene and a complex set of chromosomal aberrations, including 1p36 deletion, 11q deletion and 17q gain, are characteristic of poor prognostic neuroblastoma (reviewed in [1,2]). Despite years of intensive research, the initial steps of neuroblas- toma pathogenesis remain elusive, and contrasting re- sults have raised puzzling questions. For example, while MYCN amplification is the major adverse prognostic fac- tor, the level of MYCN expression does not correlate with outcome in neuroblastomas having the normal copy number of MYCN [3]. The absence of p53 mutations in virtually all neuroblastomas is also an intriguing fact, since p53 mutations are prevalent in most other malig- nancies [2]. With the emergence of an additional com- plex layer of gene regulation through the discovery of microRNAs, there is realistic hope for new insights into the complex pathogenesis of neuroblastoma, which may finally contribute to solving open questions and enlight- ening seemingly paradoxical results. 0304-3835/$ - see front matter Ó 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2008.06.010 * Corresponding author. Tel.: +4920172385185; fax: +492017235750. E-mail address: johannes.schulte@uni-due.de (J.H. Schulte). Cancer Letters 274 (2009) 10–15 Contents lists available at ScienceDirect Cancer Letters journal homepage: www.elsevier.com/locate/canlet