Abstract | BACKGROUND: The immune therapeutic potential of microRNAs ( miRNAs) in the context of tumor-mediated immune suppression has not been previously described for monocyte-derived glioma-associated macrophages, which are the largest infiltrating immune cell population in glioblastomas and facilitate gliomagenesis. METHODS: An miRNA microarray was used to compare expression profiles between human glioblastoma-infiltrating macrophages and matched peripheral monocytes. The effects of miR-142-3p on phenotype and function of proinflammatory M1 and immunosuppressive M2 macrophages were determined. The therapeutic effect of miR-142-3p was ascertained in immune-competent C57BL/6J mice harboring intracerebral GL261 gliomas and in genetically engineered Ntv-a mice bearing high-grade gliomas. Student t test was used to evaluate the differences between ex vivo datasets. Survival was analyzed with the log-rank test and tumor sizes with linear mixed models and F test. All statistical tests were two-sided. RESULTS: miR-142-3p was the most downregulated miRNA (approximately 4.95-fold) in glioblastoma-infiltrating macrophages. M2 macrophages had lower miR-142-3p expression relative to M1 macrophages (P = .03). Overexpression of miR-142-3p in M2 macrophages induced selective modulation of transforming growth factor beta receptor 1, which led to subsequent preferential apoptosis in the M2 subset (P = .01). In vivo miR-142-3p administration resulted in glioma growth inhibition (P = .03, n = 5) and extended median survival (miR-142-3p-treated C57BL/6J mice vs scramble control: 31 days vs 23.5 days, P = .03, n = 10; miR-142-3p treated Ntv-a mice vs scramble control: 32 days vs 24 days, P = .03, n = 9), with an associated decrease in infiltrating macrophages (R (2) = .303). CONCLUSIONS:
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Authors | Shuo Xu, Jun Wei, Fei Wang, Ling-Yuan Kong, Xiao-Yang Ling, Edjah Nduom, Konrad Gabrusiewicz, Tiffany Doucette, Yuhui Yang, Nasser K Yaghi, Virginia Fajt, Jonathan M Levine, Wei Qiao, Xin-Gang Li, Frederick F Lang, Ganesh Rao, Gregory N Fuller, George A Calin, Amy B Heimberger |
Journal | Journal of the National Cancer Institute
(J Natl Cancer Inst)
Vol. 106
Issue 8
(Aug 2014)
ISSN: 1460-2105 [Electronic] United States |
PMID | 24974128
(Publication Type: Journal Article)
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Copyright | © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected]. |
Chemical References |
- MicroRNAs
- Mirn142 microRNA, mouse
- Transforming Growth Factor beta1
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Topics |
- Animals
- Apoptosis
- Brain Neoplasms
(drug therapy, genetics, immunology)
- Cell Line, Tumor
- Down-Regulation
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Glioblastoma
(drug therapy, genetics, immunology)
- Humans
- Macrophages
(drug effects, immunology)
- Mice
- Mice, Inbred C57BL
- MicroRNAs
(immunology, pharmacology)
- Monocytes
(drug effects)
- Real-Time Polymerase Chain Reaction
- Signal Transduction
- Transforming Growth Factor beta1
(metabolism)
- Up-Regulation
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