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https://doi.org/10.1371/journal.pone.0033844
Title: | MiR-34a repression in proneural malignant gliomas upregulates expression of its target PDGFRA and promotes tumorigenesis | Authors: | Silber J. Jacobsen A. Ozawa T. Harinath G. Pedraza A. Sander C. Holland E.C. Huse J.T. |
Keywords: | microRNA microRNA 34a platelet derived growth factor platelet derived growth factor alpha receptor protein p53 unclassified drug animal experiment animal model article bioinformatics carcinogenesis cell growth cell proliferation controlled study down regulation gene regulatory network glioblastoma glioma cell growth inhibition human human tissue in vitro study in vivo study male mouse negative feedback nonhuman Animals Base Sequence Cell Cycle Checkpoints Cell Line Cell Proliferation Cell Transformation, Neoplastic Gene Expression Regulation, Neoplastic Glioma Humans Mice MicroRNAs Platelet-Derived Growth Factor Receptor, Platelet-Derived Growth Factor alpha Signal Transduction Tumor Suppressor Protein p53 |
Issue Date: | 2012 | Publisher: | Public Library of Science | Citation: | Silber J., Jacobsen A., Ozawa T., Harinath G., Pedraza A., Sander C., Holland E.C., Huse J.T. (2012). MiR-34a repression in proneural malignant gliomas upregulates expression of its target PDGFRA and promotes tumorigenesis. PLoS ONE 7 (3) : e33844. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0033844 | Abstract: | Glioblastoma (GBM) and other malignant gliomas are aggressive primary neoplasms of the brain that exhibit notable refractivity to standard treatment regimens. Recent large-scale molecular profiling has revealed distinct disease subclasses within malignant gliomas whose defining genomic features highlight dysregulated molecular networks as potential targets for therapeutic development. The "proneural" designation represents the largest and most heterogeneous of these subclasses, and includes both a large fraction of GBMs along with most of their lower-grade astrocytic and oligodendroglial counterparts. The pathogenesis of proneural gliomas has been repeatedly associated with dysregulated PDGF signaling. Nevertheless, genomic amplification or activating mutations involving the PDGF receptor (PDGFRA) characterize only a subset of proneural GBMs, while the mechanisms driving dysregulated PDGF signaling and downstream oncogenic networks in remaining tumors are unclear. MicroRNAs (miRNAs) are a class of small, noncoding RNAs that regulate gene expression by binding loosely complimentary sequences in target mRNAs. The role of miRNA biology in numerous cancer variants is well established. In an analysis of miRNA involvement in the phenotypic expression and regulation of oncogenic PDGF signaling, we found that miR-34a is downregulated by PDGF pathway activation in vitro. Similarly, analysis of data from the Cancer Genome Atlas (TCGA) revealed that miR-34a expression is significantly lower in proneural gliomas compared to other tumor subtypes. Using primary GBM cells maintained under neurosphere conditions, we then demonstrated that miR-34a specifically affects growth of proneural glioma cells in vitro and in vivo. Further bioinformatic analysis identified PDGFRA as a direct target of miR-34a and this interaction was experimentally validated. Finally, we found that PDGF-driven miR-34a repression is unlikely to operate solely through a p53-dependent mechanism. Taken together, our data support the existence of reciprocal negative feedback regulation involving miR-34 and PDGFRA expression in proneural gliomas and, as such, identify a subtype specific therapeutic potential for miR-34a. © 2012 Silber et al. | Source Title: | PLoS ONE | URI: | https://scholarbank.nus.edu.sg/handle/10635/165575 | ISSN: | 19326203 | DOI: | 10.1371/journal.pone.0033844 |
Appears in Collections: | Elements Staff Publications |
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