Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease
Peligros, Maria Isabel
Mohamed, Mohamed Ramadan
Iraburu, Maria J
Latasa, Maria Ujue
Fernández-Barrena, Maite G
Nelson, Leonard J
Davis, Roger J
Nevzorova, Yulia A
Avila, Matias A
Cubero, Francisco Javier
UMass Chan AffiliationsProgram in Molecular Medicine
Document TypeJournal Article
c-Jun N-terminal kinases (JNK)
endoplasmic reticulum (ER) stress
fibropolycystic liver disease
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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.
SourceChen C, Wu H, Ye H, Tortajada A, Rodríguez-Perales S, Torres-Ruiz R, Vidal A, Peligros MI, Reissing J, Bruns T, Mohamed MR, Zheng K, Lujambio A, Iraburu MJ, Colyn L, Latasa MU, Arechederra M, Fernández-Barrena MG, Berasain C, Vaquero J, Bañares R, Nelson LJ, Trautwein C, Davis RJ, Martinez-Naves E, Nevzorova YA, Villanueva A, Avila MA, Cubero FJ. Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease. Cancers (Basel). 2021 Dec 24;14(1):78. doi: 10.3390/cancers14010078. PMID: 35008241; PMCID: PMC8750579.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/51926
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Except where otherwise noted, this item's license is described as Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).