Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease

Fibropolycystic liver disease is characterized by hyperproliferation of the biliary epithelium and the formation of multiple dilated cysts, a process associated with unfolded protein response (UPR). In the present study, we aimed to understand the mechanisms of cyst formation and UPR activation in h...

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Autores: Chen, Chaobo, Wu, Hanghang, Ye, Hui, Tortajada, Agustín, Rodríguez Perales, Sandra, Torres Ruiz, Raúl, Vidal, August, Peligros, Maria Isabel, Reissing, Johanna, Bruns, Tony, Ramadan Mohamed, Mohamed, Zheng, Kang, Lujambio, Amaia, Iraburu, Maria J., Colyn, Leticia, Ujue Latasa, Maria, Arechederra, María, Fernández Barrena, Maite G., Berasain, Carmen, Vaquero, Javier, Bañares, Rafael, Nelson, Leonard J., Trautwein, Christian, Davis, Roger J., Martinez Naves, Eduardo, Nevzorova, Yulia A., Villanueva Garatachea, Alberto, Avila, Matías A., Cubero, Francisco Javier
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2021
País:España
Recursos:Universidad de Barcelona
Repositório:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/182754
Acesso em linha:https://hdl.handle.net/2445/182754
Access Level:Acceso aberto
Palavra-chave:Malalties del fetge
Carcinogènesi
Liver diseases
Carcinogenesis
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spelling Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver DiseaseChen, ChaoboWu, HanghangYe, HuiTortajada, AgustínRodríguez Perales, SandraTorres Ruiz, RaúlVidal, AugustPeligros, Maria IsabelReissing, JohannaBruns, TonyRamadan Mohamed, MohamedZheng, KangLujambio, AmaiaIraburu, Maria J.Colyn, LeticiaUjue Latasa, MariaArechederra, MaríaFernández Barrena, Maite G.Berasain, CarmenVaquero, JavierBañares, RafaelNelson, Leonard J.Trautwein, ChristianDavis, Roger J.Martinez Naves, EduardoNevzorova, Yulia A.Villanueva Garatachea, AlbertoAvila, Matías A.Cubero, Francisco JavierMalalties del fetgeCarcinogènesiLiver diseasesCarcinogenesisFibropolycystic liver disease is characterized by hyperproliferation of the biliary epithelium and the formation of multiple dilated cysts, a process associated with unfolded protein response (UPR). In the present study, we aimed to understand the mechanisms of cyst formation and UPR activation in hepatocytic c-Jun N-terminal kinase 1/2 (Jnk1/2) knockout mice. Floxed JNK1/2 (Jnkf/f) and Jnk∆hepa animals were sacrificed at different time points during progression of liver disease. Histological examination of specimens evidenced the presence of collagen fiber deposition, increased α-smooth muscle actin (αSMA), infiltration of CD45, CD11b and F4/80 cells and proinflammatory cytokines (Tnf, Tgfβ1) and liver injury (e.g., ALT, apoptosis and Ki67-positive cells) in Jnk∆hepa compared with Jnkf/f livers from 32 weeks of age. This was associated with activation of effectors of the UPR, including BiP/GRP78, CHOP and spliced XBP1. Tunicamycin (TM) challenge strongly induced ER stress and fibrosis in Jnk∆hepa animals compared with Jnkf/f littermates. Finally, thioacetamide (TAA) administration to Jnk∆hepa mice induced UPR activation, peribiliary fibrosis, liver injury and markers of biliary proliferation and cholangiocarcinoma (CCA). Orthoallografts of DEN/CCl4-treated Jnk∆hepa liver tissue triggered malignant CCA. Altogether, these results suggest that activation of the UPR in conjunction with fibrogenesis might trigger hepatic cystogenesis and early stages of CCA.MDPI AG2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/182754Articles publicats en revistes (Patologia i Terapèutica Experimental)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.3390/cancers14010078Cancers, 2021, vol. 14, num. 1, p. 78https://doi.org/10.3390/cancers14010078cc by (c) Chen, Chaobo et al., 2021http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1827542026-05-27T06:46:51Z
dc.title.none.fl_str_mv Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease
title Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease
spellingShingle Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease
Chen, Chaobo
Malalties del fetge
Carcinogènesi
Liver diseases
Carcinogenesis
title_short Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease
title_full Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease
title_fullStr Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease
title_full_unstemmed Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease
title_sort Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease
dc.creator.none.fl_str_mv Chen, Chaobo
Wu, Hanghang
Ye, Hui
Tortajada, Agustín
Rodríguez Perales, Sandra
Torres Ruiz, Raúl
Vidal, August
Peligros, Maria Isabel
Reissing, Johanna
Bruns, Tony
Ramadan Mohamed, Mohamed
Zheng, Kang
Lujambio, Amaia
Iraburu, Maria J.
Colyn, Leticia
Ujue Latasa, Maria
Arechederra, María
Fernández Barrena, Maite G.
Berasain, Carmen
Vaquero, Javier
Bañares, Rafael
Nelson, Leonard J.
Trautwein, Christian
Davis, Roger J.
Martinez Naves, Eduardo
Nevzorova, Yulia A.
Villanueva Garatachea, Alberto
Avila, Matías A.
Cubero, Francisco Javier
author Chen, Chaobo
author_facet Chen, Chaobo
Wu, Hanghang
Ye, Hui
Tortajada, Agustín
Rodríguez Perales, Sandra
Torres Ruiz, Raúl
Vidal, August
Peligros, Maria Isabel
Reissing, Johanna
Bruns, Tony
Ramadan Mohamed, Mohamed
Zheng, Kang
Lujambio, Amaia
Iraburu, Maria J.
Colyn, Leticia
Ujue Latasa, Maria
Arechederra, María
Fernández Barrena, Maite G.
Berasain, Carmen
Vaquero, Javier
Bañares, Rafael
Nelson, Leonard J.
Trautwein, Christian
Davis, Roger J.
Martinez Naves, Eduardo
Nevzorova, Yulia A.
Villanueva Garatachea, Alberto
Avila, Matías A.
Cubero, Francisco Javier
author_role author
author2 Wu, Hanghang
Ye, Hui
Tortajada, Agustín
Rodríguez Perales, Sandra
Torres Ruiz, Raúl
Vidal, August
Peligros, Maria Isabel
Reissing, Johanna
Bruns, Tony
Ramadan Mohamed, Mohamed
Zheng, Kang
Lujambio, Amaia
Iraburu, Maria J.
Colyn, Leticia
Ujue Latasa, Maria
Arechederra, María
Fernández Barrena, Maite G.
Berasain, Carmen
Vaquero, Javier
Bañares, Rafael
Nelson, Leonard J.
Trautwein, Christian
Davis, Roger J.
Martinez Naves, Eduardo
Nevzorova, Yulia A.
Villanueva Garatachea, Alberto
Avila, Matías A.
Cubero, Francisco Javier
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Malalties del fetge
Carcinogènesi
Liver diseases
Carcinogenesis
topic Malalties del fetge
Carcinogènesi
Liver diseases
Carcinogenesis
description Fibropolycystic liver disease is characterized by hyperproliferation of the biliary epithelium and the formation of multiple dilated cysts, a process associated with unfolded protein response (UPR). In the present study, we aimed to understand the mechanisms of cyst formation and UPR activation in hepatocytic c-Jun N-terminal kinase 1/2 (Jnk1/2) knockout mice. Floxed JNK1/2 (Jnkf/f) and Jnk∆hepa animals were sacrificed at different time points during progression of liver disease. Histological examination of specimens evidenced the presence of collagen fiber deposition, increased α-smooth muscle actin (αSMA), infiltration of CD45, CD11b and F4/80 cells and proinflammatory cytokines (Tnf, Tgfβ1) and liver injury (e.g., ALT, apoptosis and Ki67-positive cells) in Jnk∆hepa compared with Jnkf/f livers from 32 weeks of age. This was associated with activation of effectors of the UPR, including BiP/GRP78, CHOP and spliced XBP1. Tunicamycin (TM) challenge strongly induced ER stress and fibrosis in Jnk∆hepa animals compared with Jnkf/f littermates. Finally, thioacetamide (TAA) administration to Jnk∆hepa mice induced UPR activation, peribiliary fibrosis, liver injury and markers of biliary proliferation and cholangiocarcinoma (CCA). Orthoallografts of DEN/CCl4-treated Jnk∆hepa liver tissue triggered malignant CCA. Altogether, these results suggest that activation of the UPR in conjunction with fibrogenesis might trigger hepatic cystogenesis and early stages of CCA.
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/182754
url https://hdl.handle.net/2445/182754
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3390/cancers14010078
Cancers, 2021, vol. 14, num. 1, p. 78
https://doi.org/10.3390/cancers14010078
dc.rights.none.fl_str_mv cc by (c) Chen, Chaobo et al., 2021
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Chen, Chaobo et al., 2021
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI AG
publisher.none.fl_str_mv MDPI AG
dc.source.none.fl_str_mv Articles publicats en revistes (Patologia i Terapèutica Experimental)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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