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Regorafenib inhibits epithelial-mesenchymal transition and suppresses cholangiocarcinoma metastasis via YAP1-AREG axis

Cholangiocarcinoma (CCA) is a subtype of bile duct cancer usually diagnosed late with a low survival rate and no satisfactorily systemic treatment. Recently, regorafenib has been accepted as a second-line treatment for CCA patients. In this study, we investigated the potential signal transduction pa...

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Autores principales: Chang, Yu-Chan, Li, Chien-Hsiu, Chan, Ming-Hsien, Chen, Ming-Huang, Yeh, Chun-Nan, Hsiao, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9023529/
https://www.ncbi.nlm.nih.gov/pubmed/35449153
http://dx.doi.org/10.1038/s41419-022-04816-7
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author Chang, Yu-Chan
Li, Chien-Hsiu
Chan, Ming-Hsien
Chen, Ming-Huang
Yeh, Chun-Nan
Hsiao, Michael
author_facet Chang, Yu-Chan
Li, Chien-Hsiu
Chan, Ming-Hsien
Chen, Ming-Huang
Yeh, Chun-Nan
Hsiao, Michael
author_sort Chang, Yu-Chan
collection PubMed
description Cholangiocarcinoma (CCA) is a subtype of bile duct cancer usually diagnosed late with a low survival rate and no satisfactorily systemic treatment. Recently, regorafenib has been accepted as a second-line treatment for CCA patients. In this study, we investigated the potential signal transduction pathways mediated by regorafenib. We established a transcriptomic database for regorafenib-treated CCA cells using expression microarray chips. Our data indicate that regorafenib inhibits yes-associated protein 1 (YAP1) activity in various CCA cells. In addition, we demonstrated that YAP1 regulates epithelial-mesenchymal transition (EMT)-related genes, including E-cadherin and SNAI2. We further examined YAP1 activity, phosphorylation status, and expression levels of YAP1 downstream target genes in the regorafenib model. We found that regorafenib dramatically suppressed these events in CCA cells. Moreover, in vivo results revealed that regorafenib could significantly inhibit lung foci formation and tumorigenicity. Most importantly, regorafenib and amphiregulin (AREG) neutralize antibody exhibited synergistic effects against CCA cells. In a clinical setting, patients with high YAP1 and EMT expression had a worse survival rate than patients with low YAP1, and EMT expression did. In addition, we found that YAP1 upregulated the downstream target amphiregulin in CCA. Our findings suggest that AREG neutralizing antibody antibodies combined with regorafenib can reverse the CCA metastatic phenotype and EMT in vitro and in vivo. These findings provide novel therapeutic strategies to combat the metastasis of CCA.
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spelling pubmed-90235292022-04-28 Regorafenib inhibits epithelial-mesenchymal transition and suppresses cholangiocarcinoma metastasis via YAP1-AREG axis Chang, Yu-Chan Li, Chien-Hsiu Chan, Ming-Hsien Chen, Ming-Huang Yeh, Chun-Nan Hsiao, Michael Cell Death Dis Article Cholangiocarcinoma (CCA) is a subtype of bile duct cancer usually diagnosed late with a low survival rate and no satisfactorily systemic treatment. Recently, regorafenib has been accepted as a second-line treatment for CCA patients. In this study, we investigated the potential signal transduction pathways mediated by regorafenib. We established a transcriptomic database for regorafenib-treated CCA cells using expression microarray chips. Our data indicate that regorafenib inhibits yes-associated protein 1 (YAP1) activity in various CCA cells. In addition, we demonstrated that YAP1 regulates epithelial-mesenchymal transition (EMT)-related genes, including E-cadherin and SNAI2. We further examined YAP1 activity, phosphorylation status, and expression levels of YAP1 downstream target genes in the regorafenib model. We found that regorafenib dramatically suppressed these events in CCA cells. Moreover, in vivo results revealed that regorafenib could significantly inhibit lung foci formation and tumorigenicity. Most importantly, regorafenib and amphiregulin (AREG) neutralize antibody exhibited synergistic effects against CCA cells. In a clinical setting, patients with high YAP1 and EMT expression had a worse survival rate than patients with low YAP1, and EMT expression did. In addition, we found that YAP1 upregulated the downstream target amphiregulin in CCA. Our findings suggest that AREG neutralizing antibody antibodies combined with regorafenib can reverse the CCA metastatic phenotype and EMT in vitro and in vivo. These findings provide novel therapeutic strategies to combat the metastasis of CCA. Nature Publishing Group UK 2022-04-21 /pmc/articles/PMC9023529/ /pubmed/35449153 http://dx.doi.org/10.1038/s41419-022-04816-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Chang, Yu-Chan
Li, Chien-Hsiu
Chan, Ming-Hsien
Chen, Ming-Huang
Yeh, Chun-Nan
Hsiao, Michael
Regorafenib inhibits epithelial-mesenchymal transition and suppresses cholangiocarcinoma metastasis via YAP1-AREG axis
title Regorafenib inhibits epithelial-mesenchymal transition and suppresses cholangiocarcinoma metastasis via YAP1-AREG axis
title_full Regorafenib inhibits epithelial-mesenchymal transition and suppresses cholangiocarcinoma metastasis via YAP1-AREG axis
title_fullStr Regorafenib inhibits epithelial-mesenchymal transition and suppresses cholangiocarcinoma metastasis via YAP1-AREG axis
title_full_unstemmed Regorafenib inhibits epithelial-mesenchymal transition and suppresses cholangiocarcinoma metastasis via YAP1-AREG axis
title_short Regorafenib inhibits epithelial-mesenchymal transition and suppresses cholangiocarcinoma metastasis via YAP1-AREG axis
title_sort regorafenib inhibits epithelial-mesenchymal transition and suppresses cholangiocarcinoma metastasis via yap1-areg axis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9023529/
https://www.ncbi.nlm.nih.gov/pubmed/35449153
http://dx.doi.org/10.1038/s41419-022-04816-7
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