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- Title
Effect of miR-142-3p on the M2 Macrophage and Therapeutic Efficacy Against Murine Glioblastoma.
- Authors
Xu, Shuo; Wei, Jun; Wang, Fei; Kong, Ling-Yuan; Ling, Xiao-Yang; Nduom, Edjah; Gabrusiewicz, Konrad; Doucette, Tiffany; Yang, Yuhui; Yaghi, Nasser K.; Fajt, Virginia; Levine, Jonathan M.; Qiao, Wei; Li, Xin-Gang; Lang, Frederick F.; Rao, Ganesh; Fuller, Gregory N.; Calin, George A.; Heimberger, Amy B.
- 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 (R2 = .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.
- Subjects
GLIOBLASTOMA multiforme treatment; MICRORNA; IMMUNOSUPPRESSION; CANCER treatment; MACROPHAGES
- Publication
JNCI: Journal of the National Cancer Institute, 2014, Vol 106, Issue 8, p1
- ISSN
0027-8874
- Publication type
Article
- DOI
10.1093/jnci/dju162