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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MDPI AG
2021-12-01
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| author | Chaobo Chen Hanghang Wu Hui Ye Agustín Tortajada Sandra Rodríguez-Perales Raúl Torres-Ruiz August Vidal Maria Isabel Peligros Johanna Reissing Tony Bruns Mohamed Ramadan Mohamed Kang Zheng Amaia Lujambio Maria J. Iraburu Leticia Colyn Maria Ujue Latasa María Arechederra Maite G. Fernández-Barrena Carmen Berasain Javier Vaquero Rafael Bañares Leonard J. Nelson Christian Trautwein Roger J. Davis Eduardo Martinez-Naves Yulia A. Nevzorova Alberto Villanueva Matias A. Avila Francisco Javier Cubero |
| author_facet | Chaobo Chen Hanghang Wu Hui Ye Agustín Tortajada Sandra Rodríguez-Perales Raúl Torres-Ruiz August Vidal Maria Isabel Peligros Johanna Reissing Tony Bruns Mohamed Ramadan Mohamed Kang Zheng Amaia Lujambio Maria J. Iraburu Leticia Colyn Maria Ujue Latasa María Arechederra Maite G. Fernández-Barrena Carmen Berasain Javier Vaquero Rafael Bañares Leonard J. Nelson Christian Trautwein Roger J. Davis Eduardo Martinez-Naves Yulia A. Nevzorova Alberto Villanueva Matias A. Avila Francisco Javier Cubero |
| author_sort | Chaobo Chen |
| collection | DOAJ |
| 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 (<i>Jnk1/2</i>) knockout mice. Floxed JNK1/2 (<i>Jnk<sup>f/f</sup></i>) and <i>Jnk<sup>∆hepa</sup></i> 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 (<i>Tnf</i>, <i>Tgfβ1</i>) and liver injury (e.g., ALT, apoptosis and Ki67-positive cells) in <i>Jnk<sup>∆hepa</sup></i> compared with <i>Jnk<sup>f/f</sup></i> 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 <i>Jnk<sup>∆hepa</sup></i> animals compared with <i>Jnk<sup>f/f</sup></i> littermates. Finally, thioacetamide (TAA) administration to <i>Jnk<sup>∆hepa</sup></i> mice induced UPR activation, peribiliary fibrosis, liver injury and markers of biliary proliferation and cholangiocarcinoma (CCA). Orthoallografts of DEN/CCl<sub>4</sub>-treated <i>Jnk<sup>∆hepa</sup></i> 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. |
| first_indexed | 2024-03-10T03:47:44Z |
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| series | Cancers |
| spelling | doaj.art-dce904cbb41d41b5878efa7b3898fb6c2023-11-23T11:15:41ZengMDPI AGCancers2072-66942021-12-011417810.3390/cancers14010078Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver DiseaseChaobo Chen0Hanghang Wu1Hui Ye2Agustín Tortajada3Sandra Rodríguez-Perales4Raúl Torres-Ruiz5August Vidal6Maria Isabel Peligros7Johanna Reissing8Tony Bruns9Mohamed Ramadan Mohamed10Kang Zheng11Amaia Lujambio12Maria J. Iraburu13Leticia Colyn14Maria Ujue Latasa15María Arechederra16Maite G. Fernández-Barrena17Carmen Berasain18Javier Vaquero19Rafael Bañares20Leonard J. Nelson21Christian Trautwein22Roger J. Davis23Eduardo Martinez-Naves24Yulia A. Nevzorova25Alberto Villanueva26Matias A. Avila27Francisco Javier Cubero28Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, SpainDepartment of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, SpainDepartment of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, SpainDepartment of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, SpainMolecular Cytogenetics and Genome Editing Unit, Human Cancer Genetics Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, SpainMolecular Cytogenetics and Genome Editing Unit, Human Cancer Genetics Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, SpainLaboratorio de Investigación Traslacional (LRT1)-ProCURE, Institut Català d’Oncologia (ICO)-IDIBELL, L’Hospitalet de Llobregat, 08908 Barcelona, SpainInstitute of Pathology, Hospital Universitario Gregorio Marañon, 28007 Madrid, SpainDepartment of Internal Medicine III, University Hospital RWTH, 52074 Aachen, GermanyDepartment of Internal Medicine III, University Hospital RWTH, 52074 Aachen, GermanyDepartment of Internal Medicine III, University Hospital RWTH, 52074 Aachen, GermanyDepartment of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, SpainLiver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADepartment of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, SpainHepatology Program, Cima, University of Navarra, 31008 Pamplona, SpainHepatology Program, Cima, University of Navarra, 31008 Pamplona, SpainHepatology Program, Cima, University of Navarra, 31008 Pamplona, SpainHepatology Program, Cima, University of Navarra, 31008 Pamplona, SpainHepatology Program, Cima, University of Navarra, 31008 Pamplona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, SpainInstitute for Bioengineering (IBioE), Faraday Building, The University of Edinburgh, Edinburgh EH8 9AB, UKDepartment of Internal Medicine III, University Hospital RWTH, 52074 Aachen, GermanyHoward Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01655, USADepartment of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, SpainDepartment of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, SpainLaboratorio de Investigación Traslacional (LRT1)-ProCURE, Institut Català d’Oncologia (ICO)-IDIBELL, L’Hospitalet de Llobregat, 08908 Barcelona, SpainHepatology Program, Cima, University of Navarra, 31008 Pamplona, SpainDepartment of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, SpainFibropolycystic 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 (<i>Jnk1/2</i>) knockout mice. Floxed JNK1/2 (<i>Jnk<sup>f/f</sup></i>) and <i>Jnk<sup>∆hepa</sup></i> 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 (<i>Tnf</i>, <i>Tgfβ1</i>) and liver injury (e.g., ALT, apoptosis and Ki67-positive cells) in <i>Jnk<sup>∆hepa</sup></i> compared with <i>Jnk<sup>f/f</sup></i> 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 <i>Jnk<sup>∆hepa</sup></i> animals compared with <i>Jnk<sup>f/f</sup></i> littermates. Finally, thioacetamide (TAA) administration to <i>Jnk<sup>∆hepa</sup></i> mice induced UPR activation, peribiliary fibrosis, liver injury and markers of biliary proliferation and cholangiocarcinoma (CCA). Orthoallografts of DEN/CCl<sub>4</sub>-treated <i>Jnk<sup>∆hepa</sup></i> 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.https://www.mdpi.com/2072-6694/14/1/78c-Jun N-terminal kinases (JNK)fibropolycystic liver diseasecholangiocarcinoma (CCA)endoplasmic reticulum (ER) stressthioacetamide (TAA)CM272 |
| spellingShingle | Chaobo Chen Hanghang Wu Hui Ye Agustín Tortajada Sandra Rodríguez-Perales Raúl Torres-Ruiz August Vidal Maria Isabel Peligros Johanna Reissing Tony Bruns Mohamed Ramadan Mohamed Kang Zheng Amaia Lujambio Maria J. Iraburu Leticia Colyn Maria Ujue Latasa María Arechederra Maite G. Fernández-Barrena Carmen Berasain Javier Vaquero Rafael Bañares Leonard J. Nelson Christian Trautwein Roger J. Davis Eduardo Martinez-Naves Yulia A. Nevzorova Alberto Villanueva Matias A. Avila Francisco Javier Cubero Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease Cancers c-Jun N-terminal kinases (JNK) fibropolycystic liver disease cholangiocarcinoma (CCA) endoplasmic reticulum (ER) stress thioacetamide (TAA) CM272 |
| title | 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_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_sort | activation of the unfolded protein response upr is associated with cholangiocellular injury fibrosis and carcinogenesis in an experimental model of fibropolycystic liver disease |
| topic | c-Jun N-terminal kinases (JNK) fibropolycystic liver disease cholangiocarcinoma (CCA) endoplasmic reticulum (ER) stress thioacetamide (TAA) CM272 |
| url | https://www.mdpi.com/2072-6694/14/1/78 |
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