TY - JOUR
T1 - Exosome-Mediated Transfer of microRNAs Within the Tumor Microenvironment and Neuroblastoma Resistance to Chemotherapy
AU - Challagundla, Kishore B.
AU - Wise, Petra M.
AU - Neviani, Paolo
AU - Chava, Haritha
AU - Murtadha, Mariam
AU - Xu, Tong
AU - Kennedy, Rebekah
AU - Ivan, Cristina
AU - Zhang, Xinna
AU - Vannini, Ivan
AU - Fanini, Francesca
AU - Amadori, Dino
AU - Calin, George A.
AU - Hadjidaniel, Michael
AU - Shimada, Hiroyuki
AU - Jong, Ambrose
AU - Seeger, Robert C.
AU - Asgharzadeh, Shahab
AU - Goldkorn, Amir
AU - Fabbri, Muller
PY - 2015/7/1
Y1 - 2015/7/1
N2 - 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.
AB - 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.
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U2 - 10.1093/jnci/djv135
DO - 10.1093/jnci/djv135
M3 - Article
C2 - 25972604
AN - SCOPUS:84939499533
VL - 107
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
SN - 0027-8874
IS - 7
M1 - djv135
ER -