Exosome-Mediated Transfer of microRNAs Within the Tumor Microenvironment and Neuroblastoma Resistance to Chemotherapy

Kishore B. Challagundla, Petra M. Wise, Paolo Neviani, Haritha Chava, Mariam Murtadha, Tong Xu, Rebekah Kennedy, Cristina Ivan, Xinna Zhang, Ivan Vannini, Francesca Fanini, Dino Amadori, George A. Calin, Michael Hadjidaniel, Hiroyuki Shimada, Ambrose Jong, Robert C. Seeger, Shahab Asgharzadeh, Amir Goldkorn, Muller Fabbri

Research output: Contribution to journalArticlepeer-review

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). 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. Results: miR-21 mean fold change (f.c.) was 12.08±0.30 (P 3 and 76.00±39.3mm3, 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). 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-kB/exosomic miR-155/TERF1 signaling pathway.

Original languageEnglish
Article numberdjv135
JournalJournal of the National Cancer Institute
Volume107
Issue number7
DOIs
Publication statusPublished - Jul 1 2015

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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