MicroRNA profiling in human medulloblastoma

Abstract

Medulloblastoma is an aggressive brain malignancy with high incidence in childhood. Current treatment approaches have limited efficacy and severe side effects. Therefore, new risk-adapted therapeutic strategies based on molecular classification are required. MicroRNA expression analysis has emerged as a powerful tool to identify candidate molecules playing an important role in a large number of malignancies. However, no data are yet available on human primary medulloblastomas. A high throughput microRNA expression profiles was performed in human primary medulloblastoma specimens to investigate microRNA involvement in medulloblastoma carcinogenesis. We identified specific micro-RNA expression patterns which distinguish medulloblastoma differing in histotypes (anaplastic, classic and desmoplastic), in molecular features (ErbB2 or c-Myc overexpressing tumors) and in disease-risk stratification. MicroRNAs expression profile clearly differentiates medulloblastoma from either adult or fetal normal cerebellar tissues. Only a few microRNAs displayed upregulated expression, while most of them were downregulated in tumor samples, suggesting a tumor growth-inhibitory function. This property has been addressed for miR-9 and miR-125a, whose rescued expression promoted medulloblastoma cell growth arrest and apoptosis while targeting the proproliferative truncated TrkC isoform. In conclusion, misregulated microRNA expression profiles characterize human medulloblastomas, and may provide potential targets for novel therapeutic strategies.

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16INK4a

“…For example, miR‐9 is expressed at high levels in neural tissues and is essential for the development of the brain (Delaloy et al ., 2010; Uchida, 2010). miR‐9 plays a critical role in regulating the proliferation of neural progenitors and, not surprisingly, has been implicated in the development of different types of brain tumour, such as medulloblastoma and glioblastoma (Ferretti et al ., 2009; Malzkorn et al ., 2010). Several miR‐9 target genes have been described that might play a role in this context.…”

MicroRNAs and glioblastoma; the stem cell connection

“…A recent report described microRNA alterations in medulloblastoma determined by RT-PCR of 248 microRNAs in 14 medulloblastomas compared with 7 adult and fetal normal cerebellar controls. 50 This showed some similarities with gliomas, with miR-21 upregulated, and downregulation of miR-124, miR-128, and miR-7 among many others. Interestingly, miR-137, which is downregulated in glioblastoma is upregulated in meduloblastoma samples, for unknown reasons.…”

Role of MYC in Medulloblastoma

“…MicroRNAs encoded by the miR-17 92 and miR-106b 25, but not the miR-106a 363, clusters are overexpressed specifically in human and mouse SHH MBs (Ferretti et al 2009;Northcott et al 2009a;Uziel et al 2009). The miR-17 92 cluster, also called OncomiR1, was first identified in Em-MYC-induced B-cell lymphomas (He and Hannon 2004) and found to be regulated by Mycn in SHH-treated cerebellar neural progenitors (Northcott et al 2009a) and by MYC proteins in other cancers (Mendell 2008).…”