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Exosomes derived from HCC cells induce sorafenib resistance in hepatocellular carcinoma both in vivo and in vitro

BACKGROUND: Exosomes are carriers of intercellular information and regulate the tumor microenvironment. They play an important role in drug resistance by transporting RNA molecules and proteins. However, their effects on sorafenib resistance in hepatocellular carcinoma (HCC) are not completely under...

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Autores principales: Qu, Zhen, Wu, Junhua, Wu, Junyi, Luo, Dongjun, Jiang, Chunping, Ding, Yitao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045585/
https://www.ncbi.nlm.nih.gov/pubmed/27716356
http://dx.doi.org/10.1186/s13046-016-0430-z
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author Qu, Zhen
Wu, Junhua
Wu, Junyi
Luo, Dongjun
Jiang, Chunping
Ding, Yitao
author_facet Qu, Zhen
Wu, Junhua
Wu, Junyi
Luo, Dongjun
Jiang, Chunping
Ding, Yitao
author_sort Qu, Zhen
collection PubMed
description BACKGROUND: Exosomes are carriers of intercellular information and regulate the tumor microenvironment. They play an important role in drug resistance by transporting RNA molecules and proteins. However, their effects on sorafenib resistance in hepatocellular carcinoma (HCC) are not completely understood. METHODS: Exosomes were isolated from two invasive hepatoma cell lines (MHCC-97 L and MHCC-97H), and their roles in regulating sorafenib resistance in liver cancer cells as well as the underlying molecular mechanisms were determined. The exosomes were analyzed by TEM (transmission electron microscopy), DLS (dynamic light scattering) and Western blotting. Cell viability, cell death and the effects of exosomes on the HGF/c-Met/Akt signaling pathway in cancer cells were analyzed by MTT assays, FACS analysis and Western blotting, respectively. Moreover, the effects of exosomes on sorafenib resistance in vivo were investigated using a subcutaneous transplantation tumor model in athymic nude mice. RESULTS: Exosomes derived from HCC cells were of the expected size and expressed the exosomal markers CD9 and CD63. They induced sorafenib resistance in vitro by activating the HGF/c-Met/Akt signaling pathway and inhibiting sorafenib-induced apoptosis. They also induced sorafenib resistance in vivo by inhibiting sorafenib-induced apoptosis. Moreover, exosomes derived from highly invasive tumor cells had greater efficacy than that of exosomes derived from less invasive cells. CONCLUSIONS: These data reveal the important role of HCC cell-derived exosomes in the drug resistance of liver cancer cells and demonstrate the intrinsic interaction between exosomes and their targeted tumor cells. This study suggests a new strategy for improving the effectiveness of sorafenib in treating HCC.
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spelling pubmed-50455852016-10-12 Exosomes derived from HCC cells induce sorafenib resistance in hepatocellular carcinoma both in vivo and in vitro Qu, Zhen Wu, Junhua Wu, Junyi Luo, Dongjun Jiang, Chunping Ding, Yitao J Exp Clin Cancer Res Research BACKGROUND: Exosomes are carriers of intercellular information and regulate the tumor microenvironment. They play an important role in drug resistance by transporting RNA molecules and proteins. However, their effects on sorafenib resistance in hepatocellular carcinoma (HCC) are not completely understood. METHODS: Exosomes were isolated from two invasive hepatoma cell lines (MHCC-97 L and MHCC-97H), and their roles in regulating sorafenib resistance in liver cancer cells as well as the underlying molecular mechanisms were determined. The exosomes were analyzed by TEM (transmission electron microscopy), DLS (dynamic light scattering) and Western blotting. Cell viability, cell death and the effects of exosomes on the HGF/c-Met/Akt signaling pathway in cancer cells were analyzed by MTT assays, FACS analysis and Western blotting, respectively. Moreover, the effects of exosomes on sorafenib resistance in vivo were investigated using a subcutaneous transplantation tumor model in athymic nude mice. RESULTS: Exosomes derived from HCC cells were of the expected size and expressed the exosomal markers CD9 and CD63. They induced sorafenib resistance in vitro by activating the HGF/c-Met/Akt signaling pathway and inhibiting sorafenib-induced apoptosis. They also induced sorafenib resistance in vivo by inhibiting sorafenib-induced apoptosis. Moreover, exosomes derived from highly invasive tumor cells had greater efficacy than that of exosomes derived from less invasive cells. CONCLUSIONS: These data reveal the important role of HCC cell-derived exosomes in the drug resistance of liver cancer cells and demonstrate the intrinsic interaction between exosomes and their targeted tumor cells. This study suggests a new strategy for improving the effectiveness of sorafenib in treating HCC. BioMed Central 2016-09-30 /pmc/articles/PMC5045585/ /pubmed/27716356 http://dx.doi.org/10.1186/s13046-016-0430-z Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Qu, Zhen
Wu, Junhua
Wu, Junyi
Luo, Dongjun
Jiang, Chunping
Ding, Yitao
Exosomes derived from HCC cells induce sorafenib resistance in hepatocellular carcinoma both in vivo and in vitro
title Exosomes derived from HCC cells induce sorafenib resistance in hepatocellular carcinoma both in vivo and in vitro
title_full Exosomes derived from HCC cells induce sorafenib resistance in hepatocellular carcinoma both in vivo and in vitro
title_fullStr Exosomes derived from HCC cells induce sorafenib resistance in hepatocellular carcinoma both in vivo and in vitro
title_full_unstemmed Exosomes derived from HCC cells induce sorafenib resistance in hepatocellular carcinoma both in vivo and in vitro
title_short Exosomes derived from HCC cells induce sorafenib resistance in hepatocellular carcinoma both in vivo and in vitro
title_sort exosomes derived from hcc cells induce sorafenib resistance in hepatocellular carcinoma both in vivo and in vitro
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045585/
https://www.ncbi.nlm.nih.gov/pubmed/27716356
http://dx.doi.org/10.1186/s13046-016-0430-z
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