Chaobo, ChenHanghang, WuHui, YeTortajada Alonso, AgustínPeligros Gómez, María IsabelKang, ZhengVaquero Martín, Francisco JavierBañares Cañizares, RafaelMartínez Naves, EduardoNevzorova, YuliaCubero Palero, Francisco Javier2024-01-092024-01-0920212072-669410.3390/cancers14010078https://hdl.handle.net/20.500.14352/91998Fibropolycystic 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.engAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/journal articlehttps://www.doi.org/10.3390/cancers14010078https://www.mdpi.com/2072-6694/14/1/78open access612.017c-Jun N-terminal kinases (JNK)Fibropolycystic liver diseaseCholangiocarcinoma (CCA)Endoplasmic reticulum (ER) stressThioacetamide (TAA)CM272Ciencias Biomédicas2412 Inmunología