Brain Enriched MicroRNA 128a and 9/9+: Impact on medulloblastoma pathogenesis

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DESCRIPTION (provided by applicant): Brain tumors are the leading cause of death from cancer in children under the age of 15 years. Medulloblastoma is the most common malignant brain tumor of childhood with poor outcomes and significant therapy related morbidity. Our objective is to understand the role of brain enriched microRNAs in medulloblastoma pathogenesis. MicroRNAs are small non-coding RNAs that regulate cell homeostasis by inhibiting translation or degrading mRNA of target genes. MicroRNAs can act as tumor supressor genes or oncogenes. Using miRNA microarray analysis we observed differential regulation of microRNAs in medulloblastoma compared to normal cerebellum. We propose to investigate the role of three specific brain enriched microRNAs, 128a, 9 and 9*, in medulloblastoma, particularly with respect to their impact on cerebellar stem cell and medulloblastoma cell proliferation. In Specific Aim 1, we will test our hypothsis that microRNA 128a and 9/9* will inhibit proliferation of medulloblastoma cells and potentiate differentiation. In this context we will identify and validate the potential targets of microRNA 128a in medulloblastoma (Aim 2). Based on preliminary analysis we hypothesize that microRNA 128a targets cell cycle regulator BMI1. Medulloblastoma can arise from cerebellar stem cells. In Specific Aim 3, we propose to test our hypothesis that microRNAs 128a and 9/9* will attenuate the oncogenic transformation of cerebellar neural stem cells in vivo. The long-term plan for this K08 training grant is for the PI (Dr. Vibhakar) to develop expertise in the application of molecular biology tools and in vivo models to pediatric brain tumors. The training period will enhance the didactic and practical experience of the PI. By the end of the training period Dr. Vibhakar will be poised as an independent clinician-scientist to contribute to advancing therapy in pediatric neurooncology. Relevance to public health: Alterations in the control of normal gene expression is associated with cancer. MicroRNAs have recently emerged as a significant mechanism in the control of gene expression in normal and malignant tissues. Little is known about how these molecules function in medulloblastoma formation and what genes they regulate. This study will help to understand their role in this devastating brain tumor of children and may enhance diagnosis and therapy in the future.