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Loss of c‐Jun N‐terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma

Targeted inhibition of the c‐Jun N‐terminal kinases (JNKs) has shown therapeutic potential in intrahepatic cholangiocarcinoma (CCA)‐related tumorigenesis. However, the cell‐type‐specific role and mechanisms triggered by JNK in liver parenchymal cells during CCA remain largely unknown. Here, we aimed...

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Autores principales: Cubero, Francisco Javier, Mohamed, Mohamed Ramadan, Woitok, Marius M., Zhao, Gang, Hatting, Maximilian, Nevzorova, Yulia A., Chen, Chaobo, Haybaeck, Johannes, de Bruin, Alain, Avila, Matias A., Boekschoten, Mark V., Davis, Roger J., Trautwein, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262317/
https://www.ncbi.nlm.nih.gov/pubmed/32490320
http://dx.doi.org/10.1002/hep4.1495
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author Cubero, Francisco Javier
Mohamed, Mohamed Ramadan
Woitok, Marius M.
Zhao, Gang
Hatting, Maximilian
Nevzorova, Yulia A.
Chen, Chaobo
Haybaeck, Johannes
de Bruin, Alain
Avila, Matias A.
Boekschoten, Mark V.
Davis, Roger J.
Trautwein, Christian
author_facet Cubero, Francisco Javier
Mohamed, Mohamed Ramadan
Woitok, Marius M.
Zhao, Gang
Hatting, Maximilian
Nevzorova, Yulia A.
Chen, Chaobo
Haybaeck, Johannes
de Bruin, Alain
Avila, Matias A.
Boekschoten, Mark V.
Davis, Roger J.
Trautwein, Christian
author_sort Cubero, Francisco Javier
collection PubMed
description Targeted inhibition of the c‐Jun N‐terminal kinases (JNKs) has shown therapeutic potential in intrahepatic cholangiocarcinoma (CCA)‐related tumorigenesis. However, the cell‐type‐specific role and mechanisms triggered by JNK in liver parenchymal cells during CCA remain largely unknown. Here, we aimed to investigate the relevance of JNK1 and JNK2 function in hepatocytes in two different models of experimental carcinogenesis, the dethylnitrosamine (DEN) model and in nuclear factor kappa B essential modulator (NEMO)(hepatocyte‐specific knockout (Δhepa)) mice, focusing on liver damage, cell death, compensatory proliferation, fibrogenesis, and tumor development. Moreover, regulation of essential genes was assessed by reverse transcription polymerase chain reaction, immunoblottings, and immunostainings. Additionally, specific Jnk2 inhibition in hepatocytes of NEMO(Δhepa)/JNK1(Δhepa) mice was performed using small interfering (si) RNA (siJnk2) nanodelivery. Finally, active signaling pathways were blocked using specific inhibitors. Compound deletion of Jnk1 and Jnk2 in hepatocytes diminished hepatocellular carcinoma (HCC) in both the DEN model and in NEMO(Δhepa) mice but in contrast caused massive proliferation of the biliary ducts. Indeed, Jnk1/2 deficiency in hepatocytes of NEMO(Δhepa) (NEMO(Δhepa)/JNK(Δhepa)) animals caused elevated fibrosis, increased apoptosis, increased compensatory proliferation, and elevated inflammatory cytokines expression but reduced HCC. Furthermore, siJnk2 treatment in NEMO(Δhepa)/JNK1(Δhepa) mice recapitulated the phenotype of NEMO(Δhepa)/JNK(Δhepa) mice. Next, we sought to investigate the impact of molecular pathways in response to compound JNK deficiency in NEMO(Δhepa) mice. We found that NEMO(Δhepa)/JNK(Δhepa) livers exhibited overexpression of the interleukin‐6/signal transducer and activator of transcription 3 pathway in addition to epidermal growth factor receptor (EGFR)‐rapidly accelerated fibrosarcoma (Raf)‐mitogen‐activated protein kinase kinase (MEK)‐extracellular signal‐regulated kinase (ERK) cascade. The functional relevance was tested by administering lapatinib, which is a dual tyrosine kinase inhibitor of erythroblastic oncogene B‐2 (ErbB2) and EGFR signaling, to NEMO(Δhepa)/JNK(Δhepa) mice. Lapatinib effectively inhibited cystogenesis, improved transaminases, and effectively blocked EGFR‐Raf‐MEK‐ERK signaling. Conclusion: We define a novel function of JNK1/2 in cholangiocyte hyperproliferation. This opens new therapeutic avenues devised to inhibit pathways of cholangiocarcinogenesis.
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spelling pubmed-72623172020-06-01 Loss of c‐Jun N‐terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma Cubero, Francisco Javier Mohamed, Mohamed Ramadan Woitok, Marius M. Zhao, Gang Hatting, Maximilian Nevzorova, Yulia A. Chen, Chaobo Haybaeck, Johannes de Bruin, Alain Avila, Matias A. Boekschoten, Mark V. Davis, Roger J. Trautwein, Christian Hepatol Commun Original Articles Targeted inhibition of the c‐Jun N‐terminal kinases (JNKs) has shown therapeutic potential in intrahepatic cholangiocarcinoma (CCA)‐related tumorigenesis. However, the cell‐type‐specific role and mechanisms triggered by JNK in liver parenchymal cells during CCA remain largely unknown. Here, we aimed to investigate the relevance of JNK1 and JNK2 function in hepatocytes in two different models of experimental carcinogenesis, the dethylnitrosamine (DEN) model and in nuclear factor kappa B essential modulator (NEMO)(hepatocyte‐specific knockout (Δhepa)) mice, focusing on liver damage, cell death, compensatory proliferation, fibrogenesis, and tumor development. Moreover, regulation of essential genes was assessed by reverse transcription polymerase chain reaction, immunoblottings, and immunostainings. Additionally, specific Jnk2 inhibition in hepatocytes of NEMO(Δhepa)/JNK1(Δhepa) mice was performed using small interfering (si) RNA (siJnk2) nanodelivery. Finally, active signaling pathways were blocked using specific inhibitors. Compound deletion of Jnk1 and Jnk2 in hepatocytes diminished hepatocellular carcinoma (HCC) in both the DEN model and in NEMO(Δhepa) mice but in contrast caused massive proliferation of the biliary ducts. Indeed, Jnk1/2 deficiency in hepatocytes of NEMO(Δhepa) (NEMO(Δhepa)/JNK(Δhepa)) animals caused elevated fibrosis, increased apoptosis, increased compensatory proliferation, and elevated inflammatory cytokines expression but reduced HCC. Furthermore, siJnk2 treatment in NEMO(Δhepa)/JNK1(Δhepa) mice recapitulated the phenotype of NEMO(Δhepa)/JNK(Δhepa) mice. Next, we sought to investigate the impact of molecular pathways in response to compound JNK deficiency in NEMO(Δhepa) mice. We found that NEMO(Δhepa)/JNK(Δhepa) livers exhibited overexpression of the interleukin‐6/signal transducer and activator of transcription 3 pathway in addition to epidermal growth factor receptor (EGFR)‐rapidly accelerated fibrosarcoma (Raf)‐mitogen‐activated protein kinase kinase (MEK)‐extracellular signal‐regulated kinase (ERK) cascade. The functional relevance was tested by administering lapatinib, which is a dual tyrosine kinase inhibitor of erythroblastic oncogene B‐2 (ErbB2) and EGFR signaling, to NEMO(Δhepa)/JNK(Δhepa) mice. Lapatinib effectively inhibited cystogenesis, improved transaminases, and effectively blocked EGFR‐Raf‐MEK‐ERK signaling. Conclusion: We define a novel function of JNK1/2 in cholangiocyte hyperproliferation. This opens new therapeutic avenues devised to inhibit pathways of cholangiocarcinogenesis. John Wiley and Sons Inc. 2020-04-16 /pmc/articles/PMC7262317/ /pubmed/32490320 http://dx.doi.org/10.1002/hep4.1495 Text en © 2020 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Cubero, Francisco Javier
Mohamed, Mohamed Ramadan
Woitok, Marius M.
Zhao, Gang
Hatting, Maximilian
Nevzorova, Yulia A.
Chen, Chaobo
Haybaeck, Johannes
de Bruin, Alain
Avila, Matias A.
Boekschoten, Mark V.
Davis, Roger J.
Trautwein, Christian
Loss of c‐Jun N‐terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma
title Loss of c‐Jun N‐terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma
title_full Loss of c‐Jun N‐terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma
title_fullStr Loss of c‐Jun N‐terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma
title_full_unstemmed Loss of c‐Jun N‐terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma
title_short Loss of c‐Jun N‐terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma
title_sort loss of c‐jun n‐terminal kinase 1 and 2 function in liver epithelial cells triggers biliary hyperproliferation resembling cholangiocarcinoma
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262317/
https://www.ncbi.nlm.nih.gov/pubmed/32490320
http://dx.doi.org/10.1002/hep4.1495
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