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miR‐181a induces sorafenib resistance of hepatocellular carinoma cells through downregulation of RASSF1 expression

Sorafenib, a multi‐kinase inhibitor, is the only standard clinical drug for patients with advanced hepatocellular carcinoma (HCC); however, development of sorafenib resistance in HCC often prevents its long‐term efficacy. Therefore, novel targets and strategies are urgently needed to improve the ant...

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Autores principales: Azumi, Junya, Tsubota, Toshiaki, Sakabe, Tomohiko, Shiota, Goshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021022/
https://www.ncbi.nlm.nih.gov/pubmed/27384977
http://dx.doi.org/10.1111/cas.13006
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author Azumi, Junya
Tsubota, Toshiaki
Sakabe, Tomohiko
Shiota, Goshi
author_facet Azumi, Junya
Tsubota, Toshiaki
Sakabe, Tomohiko
Shiota, Goshi
author_sort Azumi, Junya
collection PubMed
description Sorafenib, a multi‐kinase inhibitor, is the only standard clinical drug for patients with advanced hepatocellular carcinoma (HCC); however, development of sorafenib resistance in HCC often prevents its long‐term efficacy. Therefore, novel targets and strategies are urgently needed to improve the antitumor effect of sorafenib. In the present study, we examined the novel mechanisms of sorafenib resistance of HCC cells by investigating the difference in sorafenib sensitivity between two HCC cell lines. Sorafenib induced more apoptosis of HepG2 cells compared to Hep3B cells. Sorafenib exposure to HepG2 cells but not Hep3B cells increased the expression of proapoptotic factor PUMA, and activated PARP and caspase‐3. Notably, microRNA‐181a (miR‐181a) expression levels were lower in HepG2 cells than in Hep3B cells. Exogenous miR‐181a expression in HepG2 cells reduced apoptosis, whereas inhibition of miR‐181a in Hpe3B cells increased apoptosis. In addition, we demonstrated that miR‐181a directly targets RASSF1, a MAPK signaling factor, and knockdown of RASSF1 increased sorafenib resistance. Taken together, these results suggest that miR‐181a provokes sorafenib resistance through suppression of RASSF1. Our data provide important insight into the novel therapeutic strategy against sorafenib resistance of HCC cells by targeting of miR‐181a pathway.
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spelling pubmed-50210222016-09-20 miR‐181a induces sorafenib resistance of hepatocellular carinoma cells through downregulation of RASSF1 expression Azumi, Junya Tsubota, Toshiaki Sakabe, Tomohiko Shiota, Goshi Cancer Sci Original Articles Sorafenib, a multi‐kinase inhibitor, is the only standard clinical drug for patients with advanced hepatocellular carcinoma (HCC); however, development of sorafenib resistance in HCC often prevents its long‐term efficacy. Therefore, novel targets and strategies are urgently needed to improve the antitumor effect of sorafenib. In the present study, we examined the novel mechanisms of sorafenib resistance of HCC cells by investigating the difference in sorafenib sensitivity between two HCC cell lines. Sorafenib induced more apoptosis of HepG2 cells compared to Hep3B cells. Sorafenib exposure to HepG2 cells but not Hep3B cells increased the expression of proapoptotic factor PUMA, and activated PARP and caspase‐3. Notably, microRNA‐181a (miR‐181a) expression levels were lower in HepG2 cells than in Hep3B cells. Exogenous miR‐181a expression in HepG2 cells reduced apoptosis, whereas inhibition of miR‐181a in Hpe3B cells increased apoptosis. In addition, we demonstrated that miR‐181a directly targets RASSF1, a MAPK signaling factor, and knockdown of RASSF1 increased sorafenib resistance. Taken together, these results suggest that miR‐181a provokes sorafenib resistance through suppression of RASSF1. Our data provide important insight into the novel therapeutic strategy against sorafenib resistance of HCC cells by targeting of miR‐181a pathway. John Wiley and Sons Inc. 2016-09-02 2016-09 /pmc/articles/PMC5021022/ /pubmed/27384977 http://dx.doi.org/10.1111/cas.13006 Text en © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Azumi, Junya
Tsubota, Toshiaki
Sakabe, Tomohiko
Shiota, Goshi
miR‐181a induces sorafenib resistance of hepatocellular carinoma cells through downregulation of RASSF1 expression
title miR‐181a induces sorafenib resistance of hepatocellular carinoma cells through downregulation of RASSF1 expression
title_full miR‐181a induces sorafenib resistance of hepatocellular carinoma cells through downregulation of RASSF1 expression
title_fullStr miR‐181a induces sorafenib resistance of hepatocellular carinoma cells through downregulation of RASSF1 expression
title_full_unstemmed miR‐181a induces sorafenib resistance of hepatocellular carinoma cells through downregulation of RASSF1 expression
title_short miR‐181a induces sorafenib resistance of hepatocellular carinoma cells through downregulation of RASSF1 expression
title_sort mir‐181a induces sorafenib resistance of hepatocellular carinoma cells through downregulation of rassf1 expression
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021022/
https://www.ncbi.nlm.nih.gov/pubmed/27384977
http://dx.doi.org/10.1111/cas.13006
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