Department of Neurological Surgery
Amino Acids, Peptides, and Proteins | Cancer Biology | Genetic Phenomena | Neoplasms | Nucleic Acids, Nucleotides, and Nucleosides
BACKGROUND: 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. Here we show that miR-29a activates a multi-faceted growth and invasion program that promotes glioblastoma aggressiveness.
METHODS: microRNA 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.
RESULTS: Members 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.
CONCLUSIONS: Taken together, these data identify miR-29a as a master regulator of glioblastoma growth and invasion.
Glioblastoma, Invasion, PTEN, Sox4, miR-29a
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© The Author(s). 2019. Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
DOI of Published Version
J Exp Clin Cancer Res. 2019 Jan 25;38(1):36. doi: 10.1186/s13046-019-1026-1. Link to article on publisher's site
Journal of experimental and clinical cancer research : CR
Zhao Y, Huang W, Kim T, Jung Y, Menon LG, Xing H, Li H, Carroll RS, Park PJ, Yang HW, Johnson MD. (2019). MicroRNA-29a activates a multi-component growth and invasion program in glioblastoma. Open Access Articles. https://doi.org/10.1186/s13046-019-1026-1. Retrieved from https://escholarship.umassmed.edu/oapubs/3734
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.