Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in children and a leading cause of cancer-related mortality and morbidity. Several molecular sub-types of MB have been identified, suggesting they may arise from distinct cells of origin. Data from animal models indicate that some MB sub-types arise from multipotent cerebellar neural stem cells (NSCs). Hence, microRNA (miRNA) expression profiles of primary MB samples were compared to CD133+ NSCs, aiming to identify deregulated miRNAs involved in MB pathogenesis. Expression profiling of 662 miRNAs in primary MB specimens, MB cell lines, and human CD133+ NSCs and CD133− neural progenitor cells was performed by qRT-PCR. Clustering analysis identified two distinct sub-types of MB primary specimens, reminiscent of sub-types obtained from their mRNA profiles. 21 significantly up-regulated and 12 significantly down-regulated miRNAs were identified in MB primary specimens relative to CD133+ NSCs (p<0.01). The majority of up-regulated miRNAs mapped to chromosomal regions 14q32 and 17q. Integration of the predicted targets of deregulated miRNAs with mRNA expression data from the same specimens revealed enrichment of pathways regulating neuronal migration, nervous system development and cell proliferation. Transient over-expression of a down-regulated miRNA, miR-935, resulted in significant down-regulation of three of the seven predicted miR-935 target genes at the mRNA level in a MB cell line, confirming the validity of this approach. This study represents the first integrated analysis of MB miRNA and mRNA expression profiles and is the first to compare MB miRNA expression profiles to those of CD133+ NSCs. We identified several differentially expressed miRNAs that potentially target networks of genes and signaling pathways that may be involved in the transformation of normal NSCs to brain tumor stem cells. Based on this integrative approach, our data provide an important platform for future investigations aimed at characterizing the role of specific miRNAs in MB pathogenesis.
Highlights
Medulloblastoma (MB) is the most common malignant pediatric brain tumor, with an incidence of approximately 0.5 per 100 000 children less than 15 years of age [1]
Global miRNA expression analyses of primary MB specimens, MB cell lines and normal neural stem cells (NSCs) revealed four distinct clusters miRNA profiles were generated for primary MB specimens, MB cell lines, CD133+ NSCs and CD1332 neural progenitor cells (NPCs) using qRT-PCR
Cluster one consisted of CD133+ NSC and CD1332 NPC samples, which were distinct from both primary specimens and MB cell lines
Summary
Medulloblastoma (MB) is the most common malignant pediatric brain tumor, with an incidence of approximately 0.5 per 100 000 children less than 15 years of age [1]. MB is a heterogeneous disease and current risk stratification strategies often fail to accurately predict disease outcome. Recent microarray gene expression studies and genomic analyses have contributed to the improved sub-classification of MB, incorporating clinical and demographic characteristics to identify at least four distinct sub-types according to their specific gene expression signatures [7,8,9,10]. Sub-types A and B are characterized by over-active Wingless-type MMTV integration site family (Wnt) and Hedgehog (Hh) signaling respectively, while sub-types C and E exhibit enriched expression of genes associated with neuronal differentiation and photoreceptor differentiation, respectively [8]. A fifth sub-type (D) was identified, characterized by a mixed signature of both neuronal and photoreceptor differentiation. Subtype specific gene expression signatures may prove critical for the development of new targeted therapeutic agents as well as the identification of subsets of patients responsive to specific targeted therapies
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