Ex vivo miRNome analysis in Ptch1+/− cerebellum granule cells reveals a subset of miRNAs involved in radiation-induced medulloblastoma
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Barbara Tanno1,*, Gabriele Babini2,*, Simona Leonardi1, Paola Giardullo3,4, Ilaria De Stefano3, Emanuela Pasquali1, Andrea Ottolenghi2, Michael J. Atkinson5, Anna Saran1, Mariateresa Mancuso1
1Laboratory of Biomedical Technologies, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), Rome, Italy
2Department of Physics, University of Pavia, Pavia, Italy
3Department of Radiation Physics, Guglielmo Marconi University, Rome, Italy
4Department of Sciences, Roma Tre University, Rome, Italy
5Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Radiation Biology, Neuherberg, Germany
*These authors contributed equally to this work
Mariateresa Mancuso, email: [email protected]
Anna Saran, email: [email protected]
Keywords: miRNA, X-rays, medulloblastoma, Shh, GCPs
Received: June 08, 2016 Accepted: September 05, 2016 Published: September 10, 2016
It has historically been accepted that incorrectly repaired DNA double strand breaks (DSBs) are the principal lesions of importance regarding mutagenesis, and long-term biological effects associated with ionizing radiation. However, radiation may also cause dysregulation of epigenetic processes that can lead to altered gene function and malignant transformation, and epigenetic alterations are important causes of miRNAs dysregulation in cancer.
Patched1 heterozygous (Ptch1+/−) mice, characterized by aberrant activation of the Sonic hedgehog (Shh) signaling pathway, are a well-known murine model of spontaneous and radiation-induced medulloblastoma (MB), a common pediatric brain tumor originating from neural granule cell progenitors (GCPs). The high sensitivity of neonatal Ptch1+/− mice to radiogenic MB is dependent on deregulation of the Ptch1 gene function. Ptch1 activates a growth and differentiation programme that is a strong candidate for regulation through the non-coding genome. Therefore we carried out miRNA next generation sequencing in ex vivo irradiated and control GCPs, isolated and purified from cerebella of neonatal WT and Ptch1+/− mice. We identified a subset of miRNAs, namely let-7 family and miR-17~92 cluster members, whose expression is altered in GCPs by radiation alone, or by synergistic interaction of radiation with Shh-deregulation. The same miRNAs were further validated in spontaneous and radiation-induced MBs from Ptch1+/− mice, confirming persistent deregulation of these miRNAs in the pathogenesis of MB.
Our results support the hypothesis that miRNAs dysregulation is associated with radiosensitivity of GCPs and their neoplastic transformation in vivo.
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