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

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dc.contributor.authorChaobo, Chen
dc.contributor.authorHanghang,Wu
dc.contributor.authorHui, Ye
dc.contributor.authorTortajada Alonso, Agustín
dc.contributor.authorPeligros Gómez, María Isabel
dc.contributor.authorKang ,Zheng
dc.contributor.authorVaquero Martín, Francisco Javier
dc.contributor.authorBañares Cañizares, Rafael
dc.contributor.authorMartínez Naves, Eduardo
dc.contributor.authorNevzorova, Yulia
dc.contributor.authorCubero Palero, Francisco Javier
dc.date.accessioned2024-01-09T11:38:43Z
dc.date.available2024-01-09T11:38:43Z
dc.date.issued2021
dc.description.abstractFibropolycystic 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.departmentDepto. de Inmunología, Oftalmología y ORL
dc.description.facultyFac. de Medicina
dc.description.refereedTRUE
dc.description.sponsorshipMinisterio de Economía, Comercio y Empresa (España)
dc.description.sponsorshipGerman Research Foundation
dc.description.statuspub
dc.identifier.doi10.3390/cancers14010078
dc.identifier.issn2072-6694
dc.identifier.officialurlhttps://www.doi.org/10.3390/cancers14010078
dc.identifier.relatedurlhttps://www.mdpi.com/2072-6694/14/1/78
dc.identifier.urihttps://hdl.handle.net/20.500.14352/91998
dc.issue.number78
dc.journal.titleCancers
dc.language.isoeng
dc.publisherMDPI
dc.relation.projectIDPID2020-117941RB-IOO
dc.relation.projectIDSAF2016-78711
dc.relation.projectIDSAF2017-87919-R
dc.relation.projectIDPID2019-104878RB-100AEI/10.13039/501100011033
dc.relation.projectIDEXOHEP-CM S2017/BMD-3727
dc.relation.projectIDSFB/TRR57/P04
dc.relation.projectIDSFB 1382-403224013/A02
dc.relation.projectIDDFG NE 2128/2-1
dc.rightsAttribution 4.0 Internationalen
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subject.cdu612.017
dc.subject.keywordc-Jun N-terminal kinases (JNK)
dc.subject.keywordFibropolycystic liver disease
dc.subject.keywordCholangiocarcinoma (CCA)
dc.subject.keywordEndoplasmic reticulum (ER) stress
dc.subject.keywordThioacetamide (TAA)
dc.subject.keywordCM272
dc.subject.ucmCiencias Biomédicas
dc.subject.unesco2412 Inmunología
dc.titleActivation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number14
dspace.entity.typePublication
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