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Exosome-mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy.
- Source :
-
Journal of the National Cancer Institute [J Natl Cancer Inst] 2015 May 13; Vol. 107 (7). Date of Electronic Publication: 2015 May 13 (Print Publication: 2015). - Publication Year :
- 2015
-
Abstract
- Background: How exosomic microRNAs (miRNAs) contribute to the development of drug resistance in the context of the tumor microenvironment has not been previously described in neuroblastoma (NBL).<br />Methods: Coculture experiments were performed to assess exosomic transfer of miR-21 from NBL cells to human monocytes and miR-155 from human monocytes to NBL cells. Luciferase reporter assays were performed to assess miR-155 targeting of TERF1 in NBL cells. Tumor growth was measured in NBL xenografts treated with Cisplatin and peritumoral exosomic miR-155 (n = 6 mice per group) CD163, miR-155, and TERF1 levels were assessed in 20 NBL primary tissues by Human Exon Arrays and quantitative real-time polymerase chain reaction. Student's t test was used to evaluate the differences between treatment groups. All statistical tests were two-sided.<br />Results: miR-21 mean fold change (f.c.) was 12.08±0.30 (P < .001) in human monocytes treated with NBL derived exosomes for 48 hours, and miR-155 mean f.c. was 4.51±0.25 (P < .001) in NBL cells cocultured with human monocytes for 48 hours. TERF1 mean luciferase activity in miR-155 transfected NBL cells normalized to scrambled was 0.36 ± 0.05 (P <.001). Mean tumor volumes in Dotap-miR-155 compared with Dotap-scrambled were 322.80±120mm(3) and 76.00±39.3mm(3), P = .002 at day 24, respectively. Patients with high CD163 infiltrating NBLs had statistically significantly higher intratumoral levels of miR-155 (P = .04) and lower levels of TERF1 mRNA (P = .02).<br />Conclusions: These data indicate a unique role of exosomic miR-21 and miR-155 in the cross-talk between NBL cells and human monocytes in the resistance to chemotherapy, through a novel exosomic miR-21/TLR8-NF-кB/exosomic miR-155/TERF1 signaling pathway.<br /> (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Subjects :
- Antineoplastic Agents pharmacology
Cell Communication
Cisplatin pharmacology
Coculture Techniques
Gene Expression Regulation, Neoplastic
Heterografts
Humans
NF-kappa B metabolism
Neuroblastoma metabolism
Real-Time Polymerase Chain Reaction
Receptor Cross-Talk
Shelterin Complex
Telomere-Binding Proteins metabolism
Toll-Like Receptor 8 metabolism
Tumor Microenvironment
Drug Resistance, Neoplasm
Exosomes metabolism
MicroRNAs metabolism
Monocytes metabolism
Neuroblastoma drug therapy
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2105
- Volume :
- 107
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Journal of the National Cancer Institute
- Publication Type :
- Academic Journal
- Accession number :
- 25972604
- Full Text :
- https://doi.org/10.1093/jnci/djv135