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High mobility group box 1 promotes sorafenib resistance in HepG2 cells and in vivo

BACKGROUND: Primary liver cancer is a lethal malignancy with a high mortality worldwide. Currently, sorafenib is the most effective molecular-targeted drug against hepatocellular carcinoma (HCC). However, the sorafenib resistance rate is high. The molecular mechanism of this resistance has not been...

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Autores principales: Xiao, Yinzong, Sun, Lunquan, Fu, Yongming, Huang, Yan, Zhou, Rongrong, Hu, Xingwang, Zhou, Pengcheng, Quan, Jun, Li, Ning, Fan, Xue-Gong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731191/
https://www.ncbi.nlm.nih.gov/pubmed/29246127
http://dx.doi.org/10.1186/s12885-017-3868-2
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author Xiao, Yinzong
Sun, Lunquan
Fu, Yongming
Huang, Yan
Zhou, Rongrong
Hu, Xingwang
Zhou, Pengcheng
Quan, Jun
Li, Ning
Fan, Xue-Gong
author_facet Xiao, Yinzong
Sun, Lunquan
Fu, Yongming
Huang, Yan
Zhou, Rongrong
Hu, Xingwang
Zhou, Pengcheng
Quan, Jun
Li, Ning
Fan, Xue-Gong
author_sort Xiao, Yinzong
collection PubMed
description BACKGROUND: Primary liver cancer is a lethal malignancy with a high mortality worldwide. Currently, sorafenib is the most effective molecular-targeted drug against hepatocellular carcinoma (HCC). However, the sorafenib resistance rate is high. The molecular mechanism of this resistance has not been fully elucidated. High mobility group box 1 (HMGB1) is a multifaceted protein that plays a key role in the proliferation, apoptosis, metastasis and angiogenesis of HCC cells. In addition, HMGB1 has been suggested to contribute to chemotherapy resistance in tumours, including lung cancer, osteosarcoma, neuroblastoma, leukaemia, and colorectal cancer. This study investigated the association between HMGB1 and sorafenib resistance in HCC. METHODS: HepG2 cells with HMGB1 knockdown or overexpression were generated. The efficacy of sorafenib in these cells was tested using flow cytometry and a cell counting assay. The subcellular localization of HMGB1 in HepG2 cells following sorafenib treatment was measured by western blotting and confocal microscopy. A murine subcutaneous HCC model was generated to examine the association between HMGB1 and the sensitivity of sorafenib treatment. RESULTS: The HMGB1 knockdown cells exhibited a significantly higher apoptotic level and lower cell viability than the normal HMGB1 expressing cells following the sorafenib treatment. In addition, the cell viability observed in the HMGB1 overexpressing cells was higher than that observed in the control cells following the sorafenib intervention. Sorafenib had a better tumour inhibition effect in the HMGB1 knockdown group in vivo. The amount of mitochondrial HMGB1 decreased, while the amount of cytosolic HMGB1 increased following the exposure to sorafenib. Altogether, HMGB1 translocated from the mitochondria to the cytoplasm outside the mitochondria following the exposure of HepG2 cells to sorafenib. CONCLUSIONS: A novel potential role of HMGB1 in the regulation of sorafenib therapy resistance in HCC was observed. The knockdown of HMGB1 restores sensitivity to sorafenib and enhances HepG2 cell death, while HMGB1 overexpression blunts these effects. The translocation of HMGB1 from the mitochondria to the cytosol following sorafenib treatment provides new insight into sorafenib resistance in HCC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12885-017-3868-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-57311912017-12-19 High mobility group box 1 promotes sorafenib resistance in HepG2 cells and in vivo Xiao, Yinzong Sun, Lunquan Fu, Yongming Huang, Yan Zhou, Rongrong Hu, Xingwang Zhou, Pengcheng Quan, Jun Li, Ning Fan, Xue-Gong BMC Cancer Research Article BACKGROUND: Primary liver cancer is a lethal malignancy with a high mortality worldwide. Currently, sorafenib is the most effective molecular-targeted drug against hepatocellular carcinoma (HCC). However, the sorafenib resistance rate is high. The molecular mechanism of this resistance has not been fully elucidated. High mobility group box 1 (HMGB1) is a multifaceted protein that plays a key role in the proliferation, apoptosis, metastasis and angiogenesis of HCC cells. In addition, HMGB1 has been suggested to contribute to chemotherapy resistance in tumours, including lung cancer, osteosarcoma, neuroblastoma, leukaemia, and colorectal cancer. This study investigated the association between HMGB1 and sorafenib resistance in HCC. METHODS: HepG2 cells with HMGB1 knockdown or overexpression were generated. The efficacy of sorafenib in these cells was tested using flow cytometry and a cell counting assay. The subcellular localization of HMGB1 in HepG2 cells following sorafenib treatment was measured by western blotting and confocal microscopy. A murine subcutaneous HCC model was generated to examine the association between HMGB1 and the sensitivity of sorafenib treatment. RESULTS: The HMGB1 knockdown cells exhibited a significantly higher apoptotic level and lower cell viability than the normal HMGB1 expressing cells following the sorafenib treatment. In addition, the cell viability observed in the HMGB1 overexpressing cells was higher than that observed in the control cells following the sorafenib intervention. Sorafenib had a better tumour inhibition effect in the HMGB1 knockdown group in vivo. The amount of mitochondrial HMGB1 decreased, while the amount of cytosolic HMGB1 increased following the exposure to sorafenib. Altogether, HMGB1 translocated from the mitochondria to the cytoplasm outside the mitochondria following the exposure of HepG2 cells to sorafenib. CONCLUSIONS: A novel potential role of HMGB1 in the regulation of sorafenib therapy resistance in HCC was observed. The knockdown of HMGB1 restores sensitivity to sorafenib and enhances HepG2 cell death, while HMGB1 overexpression blunts these effects. The translocation of HMGB1 from the mitochondria to the cytosol following sorafenib treatment provides new insight into sorafenib resistance in HCC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12885-017-3868-2) contains supplementary material, which is available to authorized users. BioMed Central 2017-12-15 /pmc/articles/PMC5731191/ /pubmed/29246127 http://dx.doi.org/10.1186/s12885-017-3868-2 Text en © The Author(s). 2017 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 Article
Xiao, Yinzong
Sun, Lunquan
Fu, Yongming
Huang, Yan
Zhou, Rongrong
Hu, Xingwang
Zhou, Pengcheng
Quan, Jun
Li, Ning
Fan, Xue-Gong
High mobility group box 1 promotes sorafenib resistance in HepG2 cells and in vivo
title High mobility group box 1 promotes sorafenib resistance in HepG2 cells and in vivo
title_full High mobility group box 1 promotes sorafenib resistance in HepG2 cells and in vivo
title_fullStr High mobility group box 1 promotes sorafenib resistance in HepG2 cells and in vivo
title_full_unstemmed High mobility group box 1 promotes sorafenib resistance in HepG2 cells and in vivo
title_short High mobility group box 1 promotes sorafenib resistance in HepG2 cells and in vivo
title_sort high mobility group box 1 promotes sorafenib resistance in hepg2 cells and in vivo
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731191/
https://www.ncbi.nlm.nih.gov/pubmed/29246127
http://dx.doi.org/10.1186/s12885-017-3868-2
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