Activation of the Unfolded Protein Response (UPR) Is Associated with Cholangiocellular Injury, Fibrosis and Carcinogenesis in an Experimental Model of Fibropolycystic Liver Disease
| Autor: | Chaobo Chen, Hanghang Wu, Hui Ye, Agustín Tortajada, Sandra Rodríguez-Perales, Raúl Torres-Ruiz, August Vidal, Maria Isabel Peligros, Johanna Reissing, Tony Bruns, Mohamed Ramadan Mohamed, Kang Zheng, Amaia Lujambio, Maria J. Iraburu, Leticia Colyn, Maria Ujue Latasa, María Arechederra, Maite G. Fernández-Barrena, Carmen Berasain, Javier Vaquero, Rafael Bañares, Leonard J. Nelson, Christian Trautwein, Roger J. Davis, Eduardo Martinez-Naves, Yulia A. Nevzorova, Alberto Villanueva, Matias A. Avila, Francisco Javier Cubero |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
c-Jun N-terminal kinases (JNK) Carcinogenesis Malalties del fetge cholangiocarcinoma (CCA) Neoplasms. Tumors. Oncology. Including cancer and carcinogens endoplasmic reticulum (ER) stress Stressthioacetamide (TAA) Article Oncology fibropolycystic liver disease thioacetamide (TAA) CM272 Cholangiocarcinoma (CCA) Endoplasmic reticulum (ER) Carcinogènesi RC254-282 Liver diseases Fibropolycystic liver disease |
| Zdroj: | Cancers Dipòsit Digital de la UB Universidad de Barcelona Cancers, Vol 14, Iss 78, p 78 (2022) Cancers; Volume 14; Issue 1; Pages: 78 Dadun. Depósito Académico Digital de la Universidad de Navarra Consejo Superior de Investigaciones Científicas (CSIC) |
| ISSN: | 2072-6694 |
| Popis: | Simple Summary Polycystic liver disease (PLD) is a group of rare disorders that result from structural changes in the biliary tree development in the liver. In the present work, we studied alterations in molecular mechanisms and signaling pathways that might be responsible for these pathologies. We found that activation of the unfolded protein response, a process that occurs in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum, as well as the scarring of the liver tissue, contribute to the pathogenesis of PLD and the development of cancer. As a preclinical animal model we have used mutant mice of a specific signaling pathway, the c-Jun N-terminal kinase 1/2 (Jnk1/2). These mice resemble a perfect model for the study of PLD and early cancer development. 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 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. |
| Databáze: | OpenAIRE |
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