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Identification of MALT1 as both a prognostic factor and a potential therapeutic target of regorafenib in cholangiocarcinoma patients
Intrahepatic cholangiocarcinoma (CCA) is an aggressive cancer that lacks an effective targeted therapy. Here, we assessed the therapeutic efficacy of regorafenib in CCA, as well as elucidated its underlying mechanism. We first demonstrated that regorafenib not only inhibited growth but also induced...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768338/ https://www.ncbi.nlm.nih.gov/pubmed/29371921 http://dx.doi.org/10.18632/oncotarget.23049 |
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author | Yeh, Chun-Nan Chang, Yu-Chan Su, Yeu Shin-Shian Hsu, Dennis Cheng, Chi-Tung Wu, Ren-Chin Chung, Yi-Hsiu Chiang, Kun-Chun Yeh, Ta-Sen Lu, Meng-Lun Liu, Chun-Yu Mu-Hsin Chang, Peter Chen, Ming-Han Huang, Chi-Ying F. Hsiao, Michael Chen, Ming-Huang |
author_facet | Yeh, Chun-Nan Chang, Yu-Chan Su, Yeu Shin-Shian Hsu, Dennis Cheng, Chi-Tung Wu, Ren-Chin Chung, Yi-Hsiu Chiang, Kun-Chun Yeh, Ta-Sen Lu, Meng-Lun Liu, Chun-Yu Mu-Hsin Chang, Peter Chen, Ming-Han Huang, Chi-Ying F. Hsiao, Michael Chen, Ming-Huang |
author_sort | Yeh, Chun-Nan |
collection | PubMed |
description | Intrahepatic cholangiocarcinoma (CCA) is an aggressive cancer that lacks an effective targeted therapy. Here, we assessed the therapeutic efficacy of regorafenib in CCA, as well as elucidated its underlying mechanism. We first demonstrated that regorafenib not only inhibited growth but also induced apoptosis in human CCA cells. Subsequently, we used in silico approaches to identify MALT1 (Mucosa-associated lymphoid tissue protein 1), which plays an important role in activating NF-κB, as a potential target of regorafenib. Overexpression of Elk-1, but not Ets-1, in HuCCT1 cells markedly reduced their sensitivity to regorafenib, which might be attributed to a significant increase in MALT1 levels. Our results further demonstrated that this drug drastically inhibited MALT1 expression by suppressing the Raf/Erk/Elk-1 pathway. The efficacy of regorafenib in decreasing in vivo CCA growth was confirmed in animal models. Regorafenib efficacy was observed in two MALT1-positive CCA patients who failed to respond to several other lines of therapy. Finally, MALT1 was also identified as an independent poor prognostic factor for patients with intrahepatic CCA. In conclusion, our study identified MALT1 to be a downstream mediator of the Raf/Erk/Elk-1 pathway and suggested that MALT1 may be a new therapeutic target for successful treatment of CCA by regorafenib. |
format | Online Article Text |
id | pubmed-5768338 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-57683382018-01-25 Identification of MALT1 as both a prognostic factor and a potential therapeutic target of regorafenib in cholangiocarcinoma patients Yeh, Chun-Nan Chang, Yu-Chan Su, Yeu Shin-Shian Hsu, Dennis Cheng, Chi-Tung Wu, Ren-Chin Chung, Yi-Hsiu Chiang, Kun-Chun Yeh, Ta-Sen Lu, Meng-Lun Liu, Chun-Yu Mu-Hsin Chang, Peter Chen, Ming-Han Huang, Chi-Ying F. Hsiao, Michael Chen, Ming-Huang Oncotarget Research Paper Intrahepatic cholangiocarcinoma (CCA) is an aggressive cancer that lacks an effective targeted therapy. Here, we assessed the therapeutic efficacy of regorafenib in CCA, as well as elucidated its underlying mechanism. We first demonstrated that regorafenib not only inhibited growth but also induced apoptosis in human CCA cells. Subsequently, we used in silico approaches to identify MALT1 (Mucosa-associated lymphoid tissue protein 1), which plays an important role in activating NF-κB, as a potential target of regorafenib. Overexpression of Elk-1, but not Ets-1, in HuCCT1 cells markedly reduced their sensitivity to regorafenib, which might be attributed to a significant increase in MALT1 levels. Our results further demonstrated that this drug drastically inhibited MALT1 expression by suppressing the Raf/Erk/Elk-1 pathway. The efficacy of regorafenib in decreasing in vivo CCA growth was confirmed in animal models. Regorafenib efficacy was observed in two MALT1-positive CCA patients who failed to respond to several other lines of therapy. Finally, MALT1 was also identified as an independent poor prognostic factor for patients with intrahepatic CCA. In conclusion, our study identified MALT1 to be a downstream mediator of the Raf/Erk/Elk-1 pathway and suggested that MALT1 may be a new therapeutic target for successful treatment of CCA by regorafenib. Impact Journals LLC 2017-12-08 /pmc/articles/PMC5768338/ /pubmed/29371921 http://dx.doi.org/10.18632/oncotarget.23049 Text en Copyright: © 2017 Yeh et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Yeh, Chun-Nan Chang, Yu-Chan Su, Yeu Shin-Shian Hsu, Dennis Cheng, Chi-Tung Wu, Ren-Chin Chung, Yi-Hsiu Chiang, Kun-Chun Yeh, Ta-Sen Lu, Meng-Lun Liu, Chun-Yu Mu-Hsin Chang, Peter Chen, Ming-Han Huang, Chi-Ying F. Hsiao, Michael Chen, Ming-Huang Identification of MALT1 as both a prognostic factor and a potential therapeutic target of regorafenib in cholangiocarcinoma patients |
title | Identification of MALT1 as both a prognostic factor and a potential therapeutic target of regorafenib in cholangiocarcinoma patients |
title_full | Identification of MALT1 as both a prognostic factor and a potential therapeutic target of regorafenib in cholangiocarcinoma patients |
title_fullStr | Identification of MALT1 as both a prognostic factor and a potential therapeutic target of regorafenib in cholangiocarcinoma patients |
title_full_unstemmed | Identification of MALT1 as both a prognostic factor and a potential therapeutic target of regorafenib in cholangiocarcinoma patients |
title_short | Identification of MALT1 as both a prognostic factor and a potential therapeutic target of regorafenib in cholangiocarcinoma patients |
title_sort | identification of malt1 as both a prognostic factor and a potential therapeutic target of regorafenib in cholangiocarcinoma patients |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768338/ https://www.ncbi.nlm.nih.gov/pubmed/29371921 http://dx.doi.org/10.18632/oncotarget.23049 |
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