Kishore B Challagundla1, Petra M Wise1, Paolo Neviani1, Haritha Chava1, Mariam Murtadha1, Tong Xu1, Rebekah Kennedy1, Cristina Ivan1, Xinna Zhang1, Ivan Vannini1, Francesca Fanini1, Dino Amadori1, George A Calin1, Michael Hadjidaniel1, Hiroyuki Shimada1, Ambrose Jong1, Robert C Seeger1, Shahab Asgharzadeh1, Amir Goldkorn1, Muller Fabbri2. 1. Children's Center for Cancer and Blood Diseases and The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA; and Departments of Pediatrics and Molecular Microbiology & Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA (KBC, PMW, PN, HC, MM, MF); Division of Medical Oncology, Department of Internal Medicine, University of Southern California Keck School of Medicine and Norris Comprehensive Cancer Center, Los Angeles, CA (TX, AG); Division of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, CA (RK, MH, AJ, RCS, SA); Departments of Experimental Therapeutics and Leukemia and The Center for RNA interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX (CI, GAC); Department of Gynecologic Oncology and Reproductive Medicine and The Center for RNA interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX (XZ); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) s.r.l., IRCCS, Gene Therapy Unit, Meldola (FC) 47014, Italy (IV, FF, DA); Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA (HS, SA). 2. Children's Center for Cancer and Blood Diseases and The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA; and Departments of Pediatrics and Molecular Microbiology & Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA (KBC, PMW, PN, HC, MM, MF); Division of Medical Oncology, Department of Internal Medicine, University of Southern California Keck School of Medicine and Norris Comprehensive Cancer Center, Los Angeles, CA (TX, AG); Division of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, CA (RK, MH, AJ, RCS, SA); Departments of Experimental Therapeutics and Leukemia and The Center for RNA interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX (CI, GAC); Department of Gynecologic Oncology and Reproductive Medicine and The Center for RNA interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX (XZ); Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) s.r.l., IRCCS, Gene Therapy Unit, Meldola (FC) 47014, Italy (IV, FF, DA); Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA (HS, SA). mfabbri@chla.usc.edu.
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 < .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). 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.
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 < .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). 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.
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