Abstract 1426: MiRNA expression profiling of the murine GTML medulloblastoma model reveals similarities with human tumors and identifies novel candidate miRNAs

Abstract

Abstract MicroRNAs (miRNAs) are small molecules which regulate gene expression post-transcriptionally and aberrant expression of many miRNAs is associated with different forms of cancer, including the childhood brain tumor medulloblastoma. Amplification and over-expression of either MYC or MYCN transcription factors are particularly frequent in some of the most clinically aggressive subtypes of this disease. The GTML transgenic mouse is a recently established model for highly aggressive subtypes of this tumor, in which over-expression of MYCN is targeted to the central nervous system utilizing a glutamate transporter (GLT1). Tumors exhibit two distinguishable histopathological phenotypes characteristic of specific human medulloblastoma subtypes: classic and large cell/anaplastic (LCA). Here, we evaluate the deregulation of miRNAs in tumors derived from GTML mice in order to assess the contribution of miRNAs to medulloblastoma pathogenesis. The expression of 591 miRNAs was analyzed using TaqMan low density arrays (Applied Biosystems) in 8 cerebella (controls) and 15 tumors exhibiting either LCA (n=12), and classic (n=3) phenotype. Cluster analyses performed on the overall expression of miRNAs showed a clear segregation between tumors and normal cerebella, but no definitive difference between tumor LCA and classic histopathology. We identified 37 miRNAs that were differentially expressed between tumors and controls (>2-fold; p-value< 0.05 after Bonferroni correction for multiple comparisons). Interestingly 25 of these miRNAs were conserved between mouse and human genomes, and 8 were previously associated with human medulloblastoma. Among 17 up-regulated miRNAs, four were members of the miR-17∼92a polycistronic cluster (a cluster of oncomiRs up-regulated by MYCN). We also identified miR-182, miR-96, miR-183 and miR-183*, all members of the same cluster, as up-regulated. Interestingly over-expression of miR-182 and miR-183 has been previously reported within the Wnt subtype of human medulloblastoma. Among 20 miRNAs under-expressed in the mouse tumors, miR-135a and miR-135b are conserved in human and predicted to target MYCC. Moreover miR-135a is deleted in human classic medulloblastoma with high frequency (33%). The association of miR-135b with human medulloblastoma has been previously suggested, although the role of this miRNA in medulloblastoma is controversial, since either deletion or amplification of the relevant genetic locus occurs in human tumors. Our study represents the first miRNA profiling of the recently established GTML mouse model of aggressive MYCN-driven medulloblastoma. The degree of similarity in miRNA expression observed between murine and human tumors indicates that this model is a suitable tool for the assessment of the biologic role and suitability of miRNAs as therapeutic targets in human medulloblastoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1426. doi:1538-7445.AM2012-1426