Abstract
BackgroundGlioblastoma is a malignant brain tumor characterized by rapid growth, diffuse invasion and therapeutic resistance. We recently used microRNA expression profiles to subclassify glioblastoma into five genetically and clinically distinct subclasses, and showed that microRNAs both define and contribute to the phenotypes of these subclasses. Here we show that miR-29a activates a multi-faceted growth and invasion program that promotes glioblastoma aggressiveness.MethodsmicroRNA expression profiles from 197 glioblastomas were analyzed to identify the candidate miRNAs that are correlated to glioblastoma aggressiveness. The candidate miRNA, miR-29a, was further studied in vitro and in vivo.ResultsMembers of the miR-29 subfamily display increased expression in the two glioblastoma subclasses with the worst prognoses (astrocytic and neural). We observed that miR-29a is among the microRNAs that are most positively-correlated with PTEN copy number in glioblastoma, and that miR-29a promotes glioblastoma growth and invasion in part by targeting PTEN. In PTEN-deficient glioblastoma cells, however, miR-29a nevertheless activates AKT by downregulating the metastasis suppressor, EphB3. In addition, miR-29a robustly promotes invasion in PTEN-deficient glioblastoma cells by repressing translation of the Sox4 transcription factor, and this upregulates the invasion-promoting protein, HIC5. Indeed, we identified Sox4 as the most anti-correlated predicted target of miR-29a in glioblastoma. Importantly, inhibition of endogenous miR-29a decreases glioblastoma growth and invasion in vitro and in vivo, and increased miR-29a expression in glioblastoma specimens correlates with decreased patient survival.ConclusionsTaken together, these data identify miR-29a as a master regulator of glioblastoma growth and invasion.
Highlights
Glioblastoma is a malignant brain tumor characterized by rapid growth, diffuse invasion and therapeutic resistance
Results miR-29a promotes glioblastoma growth We previously reported that patients with glioblastomas from the astrocytic and neural glioblastoma subclasses have the shortest survival among glioblastoma patients [19]
Our findings have potentially significant clinical implications. miR-29a expression is high in the astrocytic glioblastoma subclass, and this distinguishes this subclass from the other mesenchymal glioblastoma subclass
Summary
Glioblastoma is a malignant brain tumor characterized by rapid growth, diffuse invasion and therapeutic resistance. We recently used microRNA expression profiles to subclassify glioblastoma into five genetically and clinically distinct subclasses, and showed that microRNAs both define and contribute to the phenotypes of these subclasses. We show that miR-29a activates a multi-faceted growth and invasion program that promotes glioblastoma aggressiveness. One of the cancers where microRNAs have been shown to play an important role is glioblastoma, the most common and most malignant intrinsic brain tumor [18,19,20,21]. We recently used microRNA expression profiles to classify glioblastoma into five genetically and clinically distinct subclasses, and showed that microRNAs contribute significantly to the phenotypic characteristics of each subclass [19]. A growing number of microRNAs have been implicated in glioblastoma, the functional role of a majority of these molecules remains unknown
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