MiR-34a deficiency accelerates medulloblastoma formation in vivo.

Abstract

Previous studies have evaluated the role of miRNAs in cancer initiation and progression. MiR-34a was found to be downregulated in several tumors, including medulloblastomas. Here we employed targeted transgenesis to analyze the function of miR-34a in vivo. We generated mice with a constitutive deletion of the miR-34a gene. These mice were devoid of mir-34a expression in all analyzed tissues, but were viable and fertile. A comprehensive standardized phenotypic analysis including more than 300 single parameters revealed no apparent phenotype. Analysis of miR-34a expression in human medulloblastomas and medulloblastoma cell lines revealed significantly lower levels than in normal human cerebellum. Re-expression of miR-34a in human medulloblastoma cells reduced cell viability and proliferation, induced apoptosis and downregulated the miR-34a target genes, MYCN and SIRT1. Activation of the Shh pathway by targeting SmoA1 transgene overexpression causes medulloblastoma in mice, which is dependent on the presence and upregulation of Mycn. Analysis of miR-34a in medulloblastomas derived from ND2:SmoA1(tg) mice revealed significant suppression of miR-34a compared to normal cerebellum. Tumor incidence was significantly increased and tumor formation was significantly accelerated in mice transgenic for SmoA1 and lacking miR-34a. Interestingly, Mycn and Sirt1 were strongly expressed in medulloblastomas derived from these mice. We here demonstrate that miR-34a is dispensable for normal development, but that its loss accelerates medulloblastomagenesis. Strategies aiming to re-express miR-34a in tumors could, therefore, represent an efficient therapeutic option.

• Authors: Theresa Thor, Annette Künkele, Kristian W Pajtler, Annika K Wefers, Harald Stephan, Pieter Mestdagh, Lukas Heukamp, Wolfgang Hartmann, Jo Vandesompele, Natalie Sadowski, Lore Becker, Lillian Garrett, Sabine M Hölter, Marion Horsch, Julia Calzada-Wack, Tanja Klein-Rodewald, Ildiko Racz, Andreas Zimmer, Johannes Beckers, Frauke Neff, Thomas Klopstock, Pasqualino De Antonellis, Massimo Zollo, Wolfgang Wurst, Helmut Fuchs, Valérie Gailus-Durner, Ulrich Schüller, Martin Hrabě de Angelis, Angelika Eggert, Alexander Schramm, Johannes H Schulte
• Journal: International journal of cancer (Int J Cancer) Vol. 136 Issue 10 Pg. 2293-303 (May 15 2015) ISSN: 1097-0215 [Electronic] United States
• PMID: 25348795 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 UICC.

Chemical References

• MIRN34 microRNA, human
• MIRN34a microRNA, mouse
• MicroRNAs

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation
• Cerebellar Neoplasms (genetics, metabolism, pathology)
• Cerebellum (metabolism)
• Gene Expression Regulation, Neoplastic
• Gene Knockout Techniques
• Humans
• Medulloblastoma (genetics, metabolism, pathology)
• Mice
• Mice, Transgenic
• MicroRNAs (genetics, metabolism)
• Phenotype
• Signal Transduction