Pleiotropic effects of miR-183~96~182 converge to regulate cell survival, proliferation and migration in medulloblastoma

Abstract

Medulloblastomas are the most common malignant brain tumors in children. Several large-scale genomic studies have detailed their heterogeneity, defining multiple subtypes with unique molecular profiles and clinical behavior. Increased expression of the miR-183∼96∼182 cluster of microRNAs has been noted in several subgroups, including the most clinically aggressive subgroup associated with genetic amplification of MYC. To understand the contribution of miR-183∼96∼182 to the pathogenesis of this aggressive subtype of medulloblastoma, we analyzed global gene expression and proteomic changes that occur upon modulation of miRNAs in this cluster individually and as a group in MYC-amplified medulloblastoma cells. Knockdown of the full miR-183∼96∼182 cluster results in enrichment of genes associated with apoptosis and dysregulation of the PI3K/AKT/mTOR signaling axis. Conversely, there is a relative enrichment of pathways associated with migration, metastasis and epithelial to mesenchymal transition, as well as pathways associated with dysfunction of DNA repair in cells with preserved miR-183 cluster expression. Immunocytochemistry and FACS analysis confirm induction of apoptosis upon knockdown of the miR-183 cluster. Importantly, cell-based migration and invasion assays verify the positive regulation of cell motility/migration by the miR-183 cluster, which is largely mediated by miR-182. We show that the effects on cell migration induced by the miR-183 cluster are coupled to the PI3K/AKT/mTOR pathway through differential regulation of AKT1 and AKT2 isoforms. Furthermore, we show that rapamycin inhibits cell motility/migration in medulloblastoma cells and phenocopies miR-183 cluster knockdown. Thus, the miR-183 cluster regulates multiple biological programs that converge to support the maintenance and metastatic potential of medulloblastoma.

Analysis of the RNA content of the exosomes derived from blood serum and urine and its potential as biomarkers

“…Serum levels of miR-183 have been described in case/control studies where significantly lower levels of miR-183 are observed in stage IV non-small-cell lung carcinoma versus controls-making it a potential biomarker target for lung cancer [20]. In addition, a clinically aggressive medulloblastoma has been linked to the pleiotropic effects of the miR-183 cluster [21]. Conversely, miR-192 is highly represented in urine relative to serum.…”

MicroRNA Biogenesis and Hedgehog-Patched Signaling Cooperate to Regulate an Important Developmental Transition in Granule Cell Development

“…The precise role of DICER1 in medulloblastoma is less clear. For example, subsets of miRNAs have been shown as either growth-inhibitory (Ferretti et al 2008;Li et al 2009;Venkataraman et al 2013;Jin et al 2014;Hemmesi et al 2015) or oncogenic (Grunder et al 2011;Weeraratne et al 2012;Li et al 2015). In particular, the miR-1792 cluster has been shown as both necessary and sufficient to initiate medulloblastoma (Zindy et al 2014), which suggests an oncogenic role for Dicer1 on the basis of miR-1792 alone.…”

Integrative analysis of miRNA and mRNA expression profiles in pheochromocytoma and paraganglioma identifies genotype-specific markers and potentially regulated pathways

“…According to our results, the overexpression of miR-183 and/or miR-96 in PC12 cells possibly downregulates genes induced by NGF stimulation necessary for neuronal differentiation. In this regard, Weeraratne et al (2012) showed reduced viability and migration in medulloblastoma cells after miR-183 and miR-96 knockdown. These cells acquired a more flattened appearance with projections indicative of neurite outgrowth, as well as presented an increased preneuronal gene expression signature (Weeraratne et al 2012).…”