Reduced expression of brain-enriched microRNAs in glioblastomas permits targeted regulation of a cell death gene

Rebecca Skalsky, Bryan R. Cullen

Research output: Contribution to journalArticle

127 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere24248
JournalPLoS One
Volume6
Issue number9
DOIs
StatePublished - Sep 2 2011
Externally publishedYes

Fingerprint

Cell death
Glioblastoma
MicroRNAs
microRNA
cell death
Brain
Cell Death
Genes
brain
genes
thymidine kinase
herpes simplex
Thymidine Kinase
Simplexvirus
Viruses
suicide genes
RNA
Tissue
High-Throughput Nucleotide Sequencing
viruses

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Reduced expression of brain-enriched microRNAs in glioblastomas permits targeted regulation of a cell death gene. / Skalsky, Rebecca; Cullen, Bryan R.

In: PLoS One, Vol. 6, No. 9, e24248, 02.09.2011.

Research output: Contribution to journalArticle

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