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

• Published in: Cancers 2021-12, Vol.14 (1), p.78
• Main Authors: Chen, Chaobo, Wu, Hanghang, Ye, Hui, Tortajada, Agustín, Rodríguez-Perales, Sandra, Torres-Ruiz, Raúl, 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, María, Fernández-Barrena, Maite G, Berasain, Carmen, Vaquero, Javier, Bañares, Rafael, Nelson, Leonard J, Trautwein, Christian, Davis, Roger J, Martinez-Naves, Eduardo, Nevzorova, Yulia A, Villanueva, Alberto, Avila, Matias A, Cubero, Francisco Javier
• Format: Article
• Language: English
• Subjects: Actin; Animal models; Animals; Antibodies; Apoptosis; Bile ducts; c-Jun protein; Carbon tetrachloride; Carcinogenesis; CD11b antigen; CD45 antigen; Cholangiocarcinoma; Collagen; Cysts; Endoplasmic reticulum; Epithelium; Fibrosis; Gene expression; Homeostasis; Hyperplasia; Inflammation; JNK protein; Kidney diseases; Kinases; Liver cancer; Liver diseases; Molecular modelling; Protein folding; Proteins; Signal transduction; Smooth muscle; Software; Thioacetamide; Transcription factors; Tumor necrosis factor-TNF; Variance analysis
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers14010078

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 ( ) knockout mice. Floxed JNK1/2 ( ) and 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 ( , ) and liver injury (e.g., ALT, apoptosis and Ki67-positive cells) in compared with 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 animals compared with littermates. Finally, thioacetamide (TAA) administration to mice induced UPR activation, peribiliary fibrosis, liver injury and markers of biliary proliferation and cholangiocarcinoma (CCA). Orthoallografts of DEN/CCl -treated 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.