Abstract B15: Repression of PDGFRA-targeting miR-34a promotes tumorigenesis in proneural malignant gliomas

TLDR: Analysis of miRNA involvement in the phenotypic expression and regulation of oncogenic PDGF signaling found that expression of miR-34a is responsive to PDGF pathway activation in vitro, and analysis of data from the Cancer Genome Atlas revealed that expression is highly negatively correlated in proneural gliomas and ingliomas harboring amplified PDGFRA compared to other tumor subtypes.

Abstract: Malignant gliomas - particularly glioblastoma (GBM) - continue to cause a disproportionate degree of morbidity and mortality within human oncology. Recent integrated genomics has demonstrated biologically distinct subclasses within malignant glioma that transcend conventional histopathological boundaries. Perhaps the broadest of these subclassess has been termed “proneural” 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 strongly linked to dysregulated PDGF signaling; but although genomic amplification or activating mutations involving the PDGF receptor (PDGFRA) characterize a significant subset of proneural GBMs, the mechanisms driving dysregulated PDGF signaling and downstream oncogenic networks in non-amplified/mutated tumors remain unclear. MicroRNAs (miRNAs) are a class of small, noncoding RNAs that regulate gene expression on a pre-translational level by binding loosely to 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 expression of miR-34a is responsive to PDGF pathway activation in vitro. Similarly, analysis of data from the Cancer Genome Atlas (TCGA) revealed that expression of miR-34a is highly negatively correlated in proneural gliomas and in gliomas harboring amplified PDGFRA compared to other tumor subtypes. Using primary GBM cells maintained under neurosphere conditions, we then demonstrated that miR-34a specifically affects growth of proneural GBM cells in vitro and in vivo. Using data from TCGA, we identified PDGFRA as a direct target of miR-34a and validated this interaction experimentally. Finally, we provided evidence for a p53-independent mechanism mediated by PDGF signaling for negative regulation of miR-34a in proneural tumors. Taken together, our data suggest reciprocal negative feedback regulation of miR-34 and PDGFRA expression in proneural gliomas and, as such, identify a subtype specific therapeutic potential for miR-34a. Citation Format: Joachim Silber, Anders Jacobsen, Tatsuya Ozawa, Girish Harinath, Eric C. Holland, Chris Sander, Jason T. Huse. Repression of PDGFRA-targeting miR-34a promotes tumorigenesis in proneural malignant gliomas [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr B15.