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Effect of miR-142-3p on the M2 macrophage and therapeutic efficacy against murine glioblastoma.

AbstractBACKGROUND:
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:
These data indicate a unique role of miR-142-3p in glioma immunity by modulating M2 macrophages through the transforming growth factor beta signaling pathway.
AuthorsShuo 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
JournalJournal of the National Cancer Institute (J Natl Cancer Inst) Vol. 106 Issue 8 (Aug 2014) ISSN: 1460-2105 [Electronic] United States
PMID24974128 (Publication Type: Journal Article)
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
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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