title: miR-34a repression in proneural malignant gliomas upregulates expression of its target PDGFRA and promotes tumorigenesis.
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.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Joachim
authors.initials: J
authors.lastname: Silber
authors.forename: Anders
authors.initials: A
authors.lastname: Jacobsen
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ozawa
authors.forename: Girish
authors.initials: G
authors.lastname: Harinath
authors.forename: Alicia
authors.initials: A
authors.lastname: Pedraza
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.forename: Eric C
authors.initials: EC
authors.lastname: Holland
authors.forename: Jason T
authors.initials: JT
authors.lastname: Huse
mesh_terms: D000818:Animals; D001483:Base Sequence; D059447:Cell Cycle Checkpoints; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D010982:Platelet-Derived Growth Factor; D016159:Tumor Suppressor Protein p53; D020796:Receptor, Platelet-Derived Growth Factor alpha