Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease
Chen, Chaobo ; Wu, Hanghang ; Ye, Hui ; Tortajada, AgustĆn ; RodrĆguez-Perales, Sandra ; Torres-Ruiz, RaĆŗl ; Vidal, August ; Peligros, Maria Isabel ; Reissing, Johanna ; Bruns, Tony ... show 10 more
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Wu, Hanghang
Ye, Hui
Tortajada, AgustĆn
RodrĆguez-Perales, Sandra
Torres-Ruiz, RaĆŗl
Vidal, August
Peligros, Maria Isabel
Reissing, Johanna
Bruns, Tony
Mohamed, Mohamed Ramadan
Zheng, Kang
Lujambio, Amaia
Iraburu, Maria J
Colyn, Leticia
Latasa, Maria Ujue
Arechederra, MarĆa
FernƔndez-Barrena, Maite G
Berasain, Carmen
Vaquero, Javier
BaƱares, Rafael
Nelson, Leonard J
Trautwein, Christian
Davis, Roger J
Martinez-Naves, Eduardo
Nevzorova, Yulia A
Villanueva, Alberto
Avila, Matias A
Cubero, Francisco Javier
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UMass Chan Affiliations
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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 Jnkāhepa animals were sacrificed at different time points during progression of liver disease. Histological examination of specimens evidenced the presence of collagen fiber deposition, increased Ī±-smooth muscle actin (Ī±SMA), infiltration of CD45, CD11b and F4/80 cells and proinflammatory cytokines (Tnf, TgfĪ²1) and liver injury (e.g., ALT, apoptosis and Ki67-positive cells) in Jnkāhepa 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 Jnkāhepa animals compared with Jnkf/f littermates. Finally, thioacetamide (TAA) administration to Jnkāhepa mice induced UPR activation, peribiliary fibrosis, liver injury and markers of biliary proliferation and cholangiocarcinoma (CCA). Orthoallografts of DEN/CCl4-treated Jnkāhepa 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.
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Chen C, Wu H, Ye H, Tortajada A, RodrĆguez-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, FernĆ”ndez-Barrena MG, Berasain C, Vaquero J, BaƱares 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.