Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease
dc.contributor.author | Chaobo, Chen | |
dc.contributor.author | Hanghang,Wu | |
dc.contributor.author | Hui, Ye | |
dc.contributor.author | Tortajada Alonso, Agustín | |
dc.contributor.author | Peligros Gómez, María Isabel | |
dc.contributor.author | Kang ,Zheng | |
dc.contributor.author | Vaquero Martín, Francisco Javier | |
dc.contributor.author | Bañares Cañizares, Rafael | |
dc.contributor.author | Martínez Naves, Eduardo | |
dc.contributor.author | Nevzorova, Yulia | |
dc.contributor.author | Cubero Palero, Francisco Javier | |
dc.date.accessioned | 2024-01-09T11:38:43Z | |
dc.date.available | 2024-01-09T11:38:43Z | |
dc.date.issued | 2021 | |
dc.description.abstract | 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. | |
dc.description.department | Depto. de Inmunología, Oftalmología y ORL | |
dc.description.faculty | Fac. de Medicina | |
dc.description.refereed | TRUE | |
dc.description.sponsorship | Ministerio de Economía, Comercio y Empresa (España) | |
dc.description.sponsorship | German Research Foundation | |
dc.description.status | pub | |
dc.identifier.doi | 10.3390/cancers14010078 | |
dc.identifier.issn | 2072-6694 | |
dc.identifier.officialurl | https://www.doi.org/10.3390/cancers14010078 | |
dc.identifier.relatedurl | https://www.mdpi.com/2072-6694/14/1/78 | |
dc.identifier.uri | https://hdl.handle.net/20.500.14352/91998 | |
dc.issue.number | 78 | |
dc.journal.title | Cancers | |
dc.language.iso | eng | |
dc.publisher | MDPI | |
dc.relation.projectID | PID2020-117941RB-IOO | |
dc.relation.projectID | SAF2016-78711 | |
dc.relation.projectID | SAF2017-87919-R | |
dc.relation.projectID | PID2019-104878RB-100AEI/10.13039/501100011033 | |
dc.relation.projectID | EXOHEP-CM S2017/BMD-3727 | |
dc.relation.projectID | SFB/TRR57/P04 | |
dc.relation.projectID | SFB 1382-403224013/A02 | |
dc.relation.projectID | DFG NE 2128/2-1 | |
dc.rights | Attribution 4.0 International | en |
dc.rights.accessRights | open access | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject.cdu | 612.017 | |
dc.subject.keyword | c-Jun N-terminal kinases (JNK) | |
dc.subject.keyword | Fibropolycystic liver disease | |
dc.subject.keyword | Cholangiocarcinoma (CCA) | |
dc.subject.keyword | Endoplasmic reticulum (ER) stress | |
dc.subject.keyword | Thioacetamide (TAA) | |
dc.subject.keyword | CM272 | |
dc.subject.ucm | Ciencias Biomédicas | |
dc.subject.unesco | 2412 Inmunología | |
dc.title | Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease | |
dc.type | journal article | |
dc.type.hasVersion | VoR | |
dc.volume.number | 14 | |
dspace.entity.type | Publication | |
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relation.isAuthorOfPublication.latestForDiscovery | a04829df-e00a-4464-a911-4a92de97a218 |
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