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

Autor: Chen C; Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain.; 12 de Octubre Health Research Institute (imas12), 28041 Madrid, Spain.; Department of General Surgery, Wuxi Branch of Zhongda Hospital, Southeast University, Wuxi 214105, China.; Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China., Wu H; Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain., Ye H; Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain.; Department of Anesthesia, Zhongda Hospital, Southeast University, Nanjing 210008, China., Tortajada A; Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain.; 12 de Octubre Health Research Institute (imas12), 28041 Madrid, Spain., Rodríguez-Perales S; Molecular Cytogenetics and Genome Editing Unit, Human Cancer Genetics Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain., Torres-Ruiz R; Molecular Cytogenetics and Genome Editing Unit, Human Cancer Genetics Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain., Vidal A; Laboratorio de Investigación Traslacional (LRT1)-ProCURE, Institut Català d'Oncologia (ICO)-IDIBELL, L'Hospitalet de Llobregat, 08908 Barcelona, Spain., Peligros MI; Institute of Pathology, Hospital Universitario Gregorio Marañon, 28007 Madrid, Spain., Reissing J; Department of Internal Medicine III, University Hospital RWTH, 52074 Aachen, Germany., Bruns T; Department of Internal Medicine III, University Hospital RWTH, 52074 Aachen, Germany., Mohamed MR; Department of Internal Medicine III, University Hospital RWTH, 52074 Aachen, Germany., Zheng K; Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain., Lujambio A; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Iraburu MJ; Department of Biochemistry and Genetics, University of Navarra, 31008 Pamplona, Spain., Colyn L; Hepatology Program, Cima, University of Navarra, 31008 Pamplona, Spain., Latasa MU; Hepatology Program, Cima, University of Navarra, 31008 Pamplona, Spain., Arechederra M; Hepatology Program, Cima, University of Navarra, 31008 Pamplona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain.; Instituto de Investigaciones Sanitarias de Navarra-IdiSNA, 31008 Pamplona, Spain., Fernández-Barrena MG; Hepatology Program, Cima, University of Navarra, 31008 Pamplona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain.; Instituto de Investigaciones Sanitarias de Navarra-IdiSNA, 31008 Pamplona, Spain., Berasain C; Hepatology Program, Cima, University of Navarra, 31008 Pamplona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain.; Instituto de Investigaciones Sanitarias de Navarra-IdiSNA, 31008 Pamplona, Spain., Vaquero J; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain.; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28007 Madrid, Spain.; Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain., Bañares R; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain.; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28007 Madrid, Spain.; Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain., Nelson LJ; Institute for Bioengineering (IBioE), Faraday Building, The University of Edinburgh, Edinburgh EH8 9AB, UK., Trautwein C; Department of Internal Medicine III, University Hospital RWTH, 52074 Aachen, Germany., Davis RJ; Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01655, USA., Martinez-Naves E; Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain.; 12 de Octubre Health Research Institute (imas12), 28041 Madrid, Spain., Nevzorova YA; Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain.; Department of Internal Medicine III, University Hospital RWTH, 52074 Aachen, Germany.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain.; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28007 Madrid, Spain., Villanueva A; Laboratorio de Investigación Traslacional (LRT1)-ProCURE, Institut Català d'Oncologia (ICO)-IDIBELL, L'Hospitalet de Llobregat, 08908 Barcelona, Spain., Avila MA; Hepatology Program, Cima, University of Navarra, 31008 Pamplona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain.; Instituto de Investigaciones Sanitarias de Navarra-IdiSNA, 31008 Pamplona, Spain., Cubero FJ; Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, 28040 Madrid, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain.; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), 28007 Madrid, Spain.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2021 Dec 24; Vol. 14 (1). Date of Electronic Publication: 2021 Dec 24.
DOI: 10.3390/cancers14010078
Abstrakt: 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 ( Jnk f/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 Jnk f/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 Jnk f/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/CCl 4 -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.
Databáze: MEDLINE
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