Abstract
Genome-wide analysis of glioblastoma multiforme (GBM) transcriptome revealed that it can be classified into at least four clinically relevant subtypes: proneural (PN), neural, classical, and mesenchymal (MES). The gene expression patterns that are distinct in these individual GBM subtypes, may account for the GBM heterogeneity and differential response to therapy. Based on our published and preliminary data, we demonstrate that microRNA-128 (miR-128), plays a crucial role in gliomagenesis, GBM stem cells (GSCs) self-renewal and radio-sensitivity. We identified miR-128 as a GBM suppressor, and its expression is especially low in MES subtype. MiR-128 exerts its tumor suppressor role by inhibiting the expression of two components of pro-oncogenic Polycomb Repressor Complexes 1 and 2 - Bmi1 and Suz12, respectively, which are highly expressed in MES GSCs. Stable knockdown of miR-128 in PN GSCs up-regulated MES-specific gene signature while its up-regulation in MES GSCs resulted in de-repression of PN-specific signature. We argue that alterations of miR-128 levels are sufficient to cause the shift between GSC subtypes, likely through changing the activity/level of PRCs, and have significant consequence for the tumorigenicity of GSCs in vivo.
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