Reduced Expression of Brain-Enriched microRNAs in Glioblastomas Permits Targeted Regulation of a Cell Death Gene
Open accessAbstract
Glioblastoma is a highly aggressive malignant tumor involving glial cells in the human brain. We used high-throughput sequencing to comprehensively profile the small RNAs expressed in glioblastoma and non-tumor brain tissues. MicroRNAs (miRNAs) made up the large majority of small RNAs, and we identified over 400 different cellular pre-miRNAs. No known viral miRNAs were detected in any of the samples analyzed. Cluster analysis revealed several miRNAs that were significantly down-regulated in glioblastomas, including miR-128, miR-124, miR-7, miR-139, miR-95, and miR-873. Post-transcriptional editing was observed for several miRNAs, including the miR-376 family, miR-411, miR-381, and miR-379. Using the deep sequencing information, we designed a lentiviral vector expressing a cell suicide gene, the herpes simplex virus thymidine kinase (HSV-TK) gene, under the regulation of a miRNA, miR-128, that was found to be enriched in non-tumor brain tissue yet down-regulated in glioblastomas, Glioblastoma cells transduced with this vector were selectively killed when cultured in the presence of ganciclovir. Using an in vitro model to recapitulate expression of brain-enriched miRNAs, we demonstrated that neuronally differentiated SH-SY5Y cells transduced with the miRNA-regulated HSV-TK vector are protected from killing by expression of endogenous miR-128. Together, these results provide an in-depth analysis of miRNA dysregulation in glioblastoma and demonstrate the potential utility of these data in the design of miRNA-regulated therapies for the treatment of brain cancers.
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- Authors
- Skalsky, R. L., & Cullen, B. R.
- Affiliations
- Duke University (US)
- Corresponding author
- Cullen, Bryan R.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-09-02
- Volume
- 6
- Issue
- 9
- Pages
- e24248
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3166303
- OpenAlex
- W2020186279
- Cited by
- 170
- References
- 63
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 8 · 2021: 10 · 2020: 10 · 2019: 10 · 2018: 15 · 2017: 13 · 2016: 19 · 2015: 21 · 2014: 18 · 2013: 23 · 2012: 13
- FWCI
- 5.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Pediatric Brain Tumor Foundation
- National Institutes of Health
- National Cancer Institute (T32CA009111, T342-CA009111)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- glioblastoma, microRNA, miR-128, miR-124, miR-7, miR-139, miR-381, miR-379, HSV thymidine kinase, ganciclovir, neuronal differentiation, SH-SY5Y cells, small RNA profiling
- MeSH terms
- Base Sequence, Brain, Genetic Vectors, Glioblastoma, Humans, Neurons, Organ Specificity, Thymidine Kinase, Genetic Variation, Reproducibility of Results, Genetic Therapy, Down-Regulation, Cell Death, RNA Editing, DNA Primers, Herpesvirus 1, Human, MicroRNAs, Genes, Transgenic, Suicide, Cell Line, Tumor, High-Throughput Nucleotide Sequencing, Transcriptome
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