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Exosomal microRNA-32-5p induces multidrug resistance in hepatocellular carcinoma via the PI3K/Akt pathway
BACKGROUND: Multidrug resistance is the main obstacle for hepatocellular carcinoma (HCC) treatment. miR-32-5p is involved in HCC progression but its function in multidrug resistance is still unclear. Here we aim to find out the function of miR-32-5p in inducing multidrug resistance and its underlyin...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846230/ https://www.ncbi.nlm.nih.gov/pubmed/29530052 http://dx.doi.org/10.1186/s13046-018-0677-7 |
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author | Fu, Xiao Liu, Mengjie Qu, Shengyang Ma, Jiequn Zhang, Yamin Shi, Tingting Wen, Hongqing Yang, Yujuan Wang, Shuhong Wang, Jing Nan, Kejun Yao, Yu Tian, Tao |
author_facet | Fu, Xiao Liu, Mengjie Qu, Shengyang Ma, Jiequn Zhang, Yamin Shi, Tingting Wen, Hongqing Yang, Yujuan Wang, Shuhong Wang, Jing Nan, Kejun Yao, Yu Tian, Tao |
author_sort | Fu, Xiao |
collection | PubMed |
description | BACKGROUND: Multidrug resistance is the main obstacle for hepatocellular carcinoma (HCC) treatment. miR-32-5p is involved in HCC progression but its function in multidrug resistance is still unclear. Here we aim to find out the function of miR-32-5p in inducing multidrug resistance and its underlying mechanisms of transforming sensitive cell to resistant cell. METHODS: We detected the expression of miR-32-5p and PTEN in the multidrug-resistant cell line (Bel/5-FU) and the sensitive cell line (Bel7402), HCC and para-carcinoma liver tissues through real-time PCR. Dual-luciferase reporter assay verified PTEN is the target of miR-32-5p. Exosomes from sensitive and multidrug resistant cell line were obtained and confirmed through ultracentrifuge and Nano Analyzer. Gain- and loss-of-function experiments, rescue experiments, a PI3K/Akt pathway inhibitor, an exosome biogenesis inhibitor, and nude mice xenograft models were used to determine the underlying mechanisms of miR-32-5p and PTEN, as well as exosomal miR-32-5p in inducing multidrug resistance in vitro and in vivo. RESULTS: miR-32-5p was significantly elevated but PTEN was reduced in Bel/5-FU. An inverse correlation between miR-32-5p and PTEN was confirmed in HCC cell lines and patients; moreover, high expression of miR-32-5p and low expression of PTEN were positively associated with poor prognosis. Over-expression of miR-32-5p activated the PI3K/Akt pathway by suppressing PTEN and induced multidrug resistance via exosomes through promoting angiogenesis and epithelial-mesenchymal transition (EMT). CONCLUSIONS: Our study demonstrated that the multidrug-resistant cell, Bel/5-FU delivers miR-32-5p to sensitive cell, Bel7402 by exosomes and activates the PI3K/Akt pathway to further induce multidrug resistance by modulating angiogenesis and EMT. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-018-0677-7) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5846230 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-58462302018-03-15 Exosomal microRNA-32-5p induces multidrug resistance in hepatocellular carcinoma via the PI3K/Akt pathway Fu, Xiao Liu, Mengjie Qu, Shengyang Ma, Jiequn Zhang, Yamin Shi, Tingting Wen, Hongqing Yang, Yujuan Wang, Shuhong Wang, Jing Nan, Kejun Yao, Yu Tian, Tao J Exp Clin Cancer Res Research BACKGROUND: Multidrug resistance is the main obstacle for hepatocellular carcinoma (HCC) treatment. miR-32-5p is involved in HCC progression but its function in multidrug resistance is still unclear. Here we aim to find out the function of miR-32-5p in inducing multidrug resistance and its underlying mechanisms of transforming sensitive cell to resistant cell. METHODS: We detected the expression of miR-32-5p and PTEN in the multidrug-resistant cell line (Bel/5-FU) and the sensitive cell line (Bel7402), HCC and para-carcinoma liver tissues through real-time PCR. Dual-luciferase reporter assay verified PTEN is the target of miR-32-5p. Exosomes from sensitive and multidrug resistant cell line were obtained and confirmed through ultracentrifuge and Nano Analyzer. Gain- and loss-of-function experiments, rescue experiments, a PI3K/Akt pathway inhibitor, an exosome biogenesis inhibitor, and nude mice xenograft models were used to determine the underlying mechanisms of miR-32-5p and PTEN, as well as exosomal miR-32-5p in inducing multidrug resistance in vitro and in vivo. RESULTS: miR-32-5p was significantly elevated but PTEN was reduced in Bel/5-FU. An inverse correlation between miR-32-5p and PTEN was confirmed in HCC cell lines and patients; moreover, high expression of miR-32-5p and low expression of PTEN were positively associated with poor prognosis. Over-expression of miR-32-5p activated the PI3K/Akt pathway by suppressing PTEN and induced multidrug resistance via exosomes through promoting angiogenesis and epithelial-mesenchymal transition (EMT). CONCLUSIONS: Our study demonstrated that the multidrug-resistant cell, Bel/5-FU delivers miR-32-5p to sensitive cell, Bel7402 by exosomes and activates the PI3K/Akt pathway to further induce multidrug resistance by modulating angiogenesis and EMT. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-018-0677-7) contains supplementary material, which is available to authorized users. BioMed Central 2018-03-12 /pmc/articles/PMC5846230/ /pubmed/29530052 http://dx.doi.org/10.1186/s13046-018-0677-7 Text en © The Author(s). 2018 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 Fu, Xiao Liu, Mengjie Qu, Shengyang Ma, Jiequn Zhang, Yamin Shi, Tingting Wen, Hongqing Yang, Yujuan Wang, Shuhong Wang, Jing Nan, Kejun Yao, Yu Tian, Tao Exosomal microRNA-32-5p induces multidrug resistance in hepatocellular carcinoma via the PI3K/Akt pathway |
title | Exosomal microRNA-32-5p induces multidrug resistance in hepatocellular carcinoma via the PI3K/Akt pathway |
title_full | Exosomal microRNA-32-5p induces multidrug resistance in hepatocellular carcinoma via the PI3K/Akt pathway |
title_fullStr | Exosomal microRNA-32-5p induces multidrug resistance in hepatocellular carcinoma via the PI3K/Akt pathway |
title_full_unstemmed | Exosomal microRNA-32-5p induces multidrug resistance in hepatocellular carcinoma via the PI3K/Akt pathway |
title_short | Exosomal microRNA-32-5p induces multidrug resistance in hepatocellular carcinoma via the PI3K/Akt pathway |
title_sort | exosomal microrna-32-5p induces multidrug resistance in hepatocellular carcinoma via the pi3k/akt pathway |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846230/ https://www.ncbi.nlm.nih.gov/pubmed/29530052 http://dx.doi.org/10.1186/s13046-018-0677-7 |
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