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

Authors

• Shuo Xu, Affiliations of authors: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (SX, X-GL), Department of Neurosurgery (SX, JW, FW, L-YK, X-YL, EN, KG, TD, YY, FFL, GR, ABH), Department of Biostatistics (WQ), Department of Pathology (GNF), and Department of Experimental Therapeutics (GAC), University of Texas M. D. Anderson Cancer Center, Houston, TX; Baylor College of Medicine, Houston, TX (NKY); Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX (VF).
• Jun Wei, Affiliations of authors: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (SX, X-GL), Department of Neurosurgery (SX, JW, FW, L-YK, X-YL, EN, KG, TD, YY, FFL, GR, ABH), Department of Biostatistics (WQ), Department of Pathology (GNF), and Department of Experimental Therapeutics (GAC), University of Texas M. D. Anderson Cancer Center, Houston, TX; Baylor College of Medicine, Houston, TX (NKY); Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX (VF).
• Fei Wang, Affiliations of authors: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (SX, X-GL), Department of Neurosurgery (SX, JW, FW, L-YK, X-YL, EN, KG, TD, YY, FFL, GR, ABH), Department of Biostatistics (WQ), Department of Pathology (GNF), and Department of Experimental Therapeutics (GAC), University of Texas M. D. Anderson Cancer Center, Houston, TX; Baylor College of Medicine, Houston, TX (NKY); Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX (VF).
• Ling-Yuan Kong, Affiliations of authors: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (SX, X-GL), Department of Neurosurgery (SX, JW, FW, L-YK, X-YL, EN, KG, TD, YY, FFL, GR, ABH), Department of Biostatistics (WQ), Department of Pathology (GNF), and Department of Experimental Therapeutics (GAC), University of Texas M. D. Anderson Cancer Center, Houston, TX; Baylor College of Medicine, Houston, TX (NKY); Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX (VF).
• Xiao-Yang Ling, Affiliations of authors: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (SX, X-GL), Department of Neurosurgery (SX, JW, FW, L-YK, X-YL, EN, KG, TD, YY, FFL, GR, ABH), Department of Biostatistics (WQ), Department of Pathology (GNF), and Department of Experimental Therapeutics (GAC), University of Texas M. D. Anderson Cancer Center, Houston, TX; Baylor College of Medicine, Houston, TX (NKY); Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX (VF).
• Edjah Nduom, Affiliations of authors: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (SX, X-GL), Department of Neurosurgery (SX, JW, FW, L-YK, X-YL, EN, KG, TD, YY, FFL, GR, ABH), Department of Biostatistics (WQ), Department of Pathology (GNF), and Department of Experimental Therapeutics (GAC), University of Texas M. D. Anderson Cancer Center, Houston, TX; Baylor College of Medicine, Houston, TX (NKY); Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX (VF).
• Konrad Gabrusiewicz, Affiliations of authors: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (SX, X-GL), Department of Neurosurgery (SX, JW, FW, L-YK, X-YL, EN, KG, TD, YY, FFL, GR, ABH), Department of Biostatistics (WQ), Department of Pathology (GNF), and Department of Experimental Therapeutics (GAC), University of Texas M. D. Anderson Cancer Center, Houston, TX; Baylor College of Medicine, Houston, TX (NKY); Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX (VF).
• Tiffany Doucette, Affiliations of authors: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (SX, X-GL), Department of Neurosurgery (SX, JW, FW, L-YK, X-YL, EN, KG, TD, YY, FFL, GR, ABH), Department of Biostatistics (WQ), Department of Pathology (GNF), and Department of Experimental Therapeutics (GAC), University of Texas M. D. Anderson Cancer Center, Houston, TX; Baylor College of Medicine, Houston, TX (NKY); Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX (VF).
• Yuhui Yang, Affiliations of authors: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (SX, X-GL), Department of Neurosurgery (SX, JW, FW, L-YK, X-YL, EN, KG, TD, YY, FFL, GR, ABH), Department of Biostatistics (WQ), Department of Pathology (GNF), and Department of Experimental Therapeutics (GAC), University of Texas M. D. Anderson Cancer Center, Houston, TX; Baylor College of Medicine, Houston, TX (NKY); Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX (VF).
• Nasser K. Yaghi, Affiliations of authors: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (SX, X-GL), Department of Neurosurgery (SX, JW, FW, L-YK, X-YL, EN, KG, TD, YY, FFL, GR, ABH), Department of Biostatistics (WQ), Department of Pathology (GNF), and Department of Experimental Therapeutics (GAC), University of Texas M. D. Anderson Cancer Center, Houston, TX; Baylor College of Medicine, Houston, TX (NKY); Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX (VF).
• Virginia Fajt, Affiliations of authors: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (SX, X-GL), Department of Neurosurgery (SX, JW, FW, L-YK, X-YL, EN, KG, TD, YY, FFL, GR, ABH), Department of Biostatistics (WQ), Department of Pathology (GNF), and Department of Experimental Therapeutics (GAC), University of Texas M. D. Anderson Cancer Center, Houston, TX; Baylor College of Medicine, Houston, TX (NKY); Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX (VF).
• Jonathan M. Levine, Affiliations of authors: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (SX, X-GL), Department of Neurosurgery (SX, JW, FW, L-YK, X-YL, EN, KG, TD, YY, FFL, GR, ABH), Department of Biostatistics (WQ), Department of Pathology (GNF), and Department of Experimental Therapeutics (GAC), University of Texas M. D. Anderson Cancer Center, Houston, TX; Baylor College of Medicine, Houston, TX (NKY); Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX (VF).
• Wei Qiao, Affiliations of authors: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (SX, X-GL), Department of Neurosurgery (SX, JW, FW, L-YK, X-YL, EN, KG, TD, YY, FFL, GR, ABH), Department of Biostatistics (WQ), Department of Pathology (GNF), and Department of Experimental Therapeutics (GAC), University of Texas M. D. Anderson Cancer Center, Houston, TX; Baylor College of Medicine, Houston, TX (NKY); Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX (VF).
• Xin-Gang Li, Affiliations of authors: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (SX, X-GL), Department of Neurosurgery (SX, JW, FW, L-YK, X-YL, EN, KG, TD, YY, FFL, GR, ABH), Department of Biostatistics (WQ), Department of Pathology (GNF), and Department of Experimental Therapeutics (GAC), University of Texas M. D. Anderson Cancer Center, Houston, TX; Baylor College of Medicine, Houston, TX (NKY); Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX (VF).
• Frederick F. Lang, Affiliations of authors: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (SX, X-GL), Department of Neurosurgery (SX, JW, FW, L-YK, X-YL, EN, KG, TD, YY, FFL, GR, ABH), Department of Biostatistics (WQ), Department of Pathology (GNF), and Department of Experimental Therapeutics (GAC), University of Texas M. D. Anderson Cancer Center, Houston, TX; Baylor College of Medicine, Houston, TX (NKY); Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX (VF).
• Ganesh Rao, Affiliations of authors: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (SX, X-GL), Department of Neurosurgery (SX, JW, FW, L-YK, X-YL, EN, KG, TD, YY, FFL, GR, ABH), Department of Biostatistics (WQ), Department of Pathology (GNF), and Department of Experimental Therapeutics (GAC), University of Texas M. D. Anderson Cancer Center, Houston, TX; Baylor College of Medicine, Houston, TX (NKY); Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX (VF).
• Gregory N. Fuller, Affiliations of authors: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (SX, X-GL), Department of Neurosurgery (SX, JW, FW, L-YK, X-YL, EN, KG, TD, YY, FFL, GR, ABH), Department of Biostatistics (WQ), Department of Pathology (GNF), and Department of Experimental Therapeutics (GAC), University of Texas M. D. Anderson Cancer Center, Houston, TX; Baylor College of Medicine, Houston, TX (NKY); Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX (VF).
• George A. Calin, Affiliations of authors: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (SX, X-GL), Department of Neurosurgery (SX, JW, FW, L-YK, X-YL, EN, KG, TD, YY, FFL, GR, ABH), Department of Biostatistics (WQ), Department of Pathology (GNF), and Department of Experimental Therapeutics (GAC), University of Texas M. D. Anderson Cancer Center, Houston, TX; Baylor College of Medicine, Houston, TX (NKY); Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX (VF).
• Amy B. Heimberger, Affiliations of authors: Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China (SX, X-GL), Department of Neurosurgery (SX, JW, FW, L-YK, X-YL, EN, KG, TD, YY, FFL, GR, ABH), Department of Biostatistics (WQ), Department of Pathology (GNF), and Department of Experimental Therapeutics (GAC), University of Texas M. D. Anderson Cancer Center, Houston, TX; Baylor College of Medicine, Houston, TX (NKY); Texas A&M University College of Veterinary Medicine & Biomedical Sciences, College Station, TX (VF). aheimber@mdanderson.org.

Document Type

Article

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: 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.

Medical Subject Headings

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

Publication Date

8-1-2014

Publication Title

Journal of the National Cancer Institute

E-ISSN

1460-2105

Volume

106

Issue

8

PubMed ID

24974128

Digital Object Identifier (DOI)

10.1093/jnci/dju162

Recommended Citation

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.; and Heimberger, Amy B., "Effect of miR-142-3p on the M2 macrophage and therapeutic efficacy against murine glioblastoma" (2014). Neurosurgery. 1920.
https://scholar.barrowneuro.org/neurosurgery/1920