Abstract
BackgroundGlioblastoma (GB) is the most common and lethal type of primary brain tumor. Clinical outcome remains poor and is essentially palliative due to the highly invasive nature of the disease. A more thorough understanding of the molecular mechanisms that drive glioma invasion is required to limit dispersion of malignant glioma cells.Methodology/Principal FindingsWe investigated the potential role of differential expression of microRNAs (miRNA) in glioma invasion by comparing the matched large-scale, genome-wide miRNA expression profiles of migrating and migration-restricted human glioma cells. Migratory and migration-restricted cell populations from seven glioma cell lines were isolated and profiled for miRNA expression. Statistical analyses revealed a set of miRNAs common to all seven glioma cell lines that were significantly down regulated in the migrating cell population relative to cells in the migration-restricted population. Among the down-regulated miRNAs, miR-23b has been reported to target potential drivers of cell migration and invasion in other cell types. Over-expression of miR-23b significantly inhibited glioma cell migration and invasion. A bioinformatics search revealed a conserved target site within the 3′ untranslated region (UTR) of Pyk2, a non-receptor tyrosine kinase previously implicated in the regulation of glioma cell migration and invasion. Increased expression of miR-23b reduced the protein expression level of Pyk2 in glioma cells but did not significantly alter the protein expression level of the related focal adhesion kinase FAK. Expression of Pyk2 via a transcript variant missing the 3′UTR in miR-23b-expressing cells partially rescued cell migration, whereas expression of Pyk2 via a transcript containing an intact 3′UTR failed to rescue cell migration.Conclusions/SignificanceReduced expression of miR-23b enhances glioma cell migration in vitro and invasion ex vivo via modulation of Pyk2 protein expression. The data suggest that specific miRNAs may regulate glioma migration and invasion to influence the progression of this disease.
Highlights
Glioblastoma (GB) is the most common adult brain tumor and is characterized by its extensive infiltration into normal brain tissue
One of the predicted targets for miR-23b is the focal adhesion kinase Pyk2 that we have previously identified as an important regulator of glioma cell migration [24,25]
To further define the role of miR-23b in the regulation of glioma cell migration, we examined the effect of knockdown of miR-23b expression in four glioma cell lines (SF767, SNB19, T98G and U87) using an anti-miR-23b oligonucleotide
Summary
Glioblastoma (GB) is the most common adult brain tumor and is characterized by its extensive infiltration into normal brain tissue This aggressive invasion effectively precludes complete surgical resection and all but assures recurrent tumor growth. Malignant cells can invade over a significant distance in the brain parenchyma, commonly along extracellular matrices of blood vessels and nerve fiber tracts to initiate additional tumor growth. This invasive characteristic is not shared by nonglial cells that metastasize to the brain from other primary tumor sites highlighting the unique biology of invasive glioma cells. A more thorough understanding of the molecular mechanisms that drive glioma invasion is required to limit dispersion of malignant glioma cells
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