Analyses of Molecular Mechanisms underlying Medulloblastoma Oncogenesis

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Although the molecular pathogenesis of medulloblastoma (MB) remains poorly understood, the importance of the Wnt and Hedgehog developmental signaling pathways has recently become apparent. In order to further the understanding of molecular events that transform a normal cerebellar cell into a MB, we utilized the technique of suppression subtractive hybridization (SSH) to identify molecules that are dysregulated and therefore may be important in MB oncogenesis. After the subtractive hybridization of cDNA from corresponding normal cerebellar tissue, SSH libraries from both human and Ptch heterozygous murine MBs were generated. Through differential screening of the libraries, over 100 cDNA fragments up-regulated in the tumor were isolated and sequenced. These sequences were identified using the NCBI BLAST program. We selected genes involved in oncogenically important processes such as cellular proliferation, apoptosis regulation, and differentiation of the cerebellum to analyze further. Genes identified in the human MB library included Unc33-like protein (ULIP), SOX4, neuronatin, the mammalian homologue of Drosophila BarH-like 1(BARHL1), the nuclear matix protein NRP/B (ENC1), and the homeobox OTX2 gene. Genes found to be up-regulated in the murine MB included cyclin D2, thymopoietin, Musashi-1, protein phosphatase 2A inhibitor-2 (I-2PP2A), and Unc5H4 (D). Using semi-quantitative RT-PCR, the mRNA expression levels for these genes are markedly higher in human MB than in the normal cerebellum. Furthermore some genes were expressed predominantly in MB. The role played by the over-expression of these genes in the transformation of normal cells remains to be fully determined.