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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wolters Kluwer Health/LWW
2020-06-01
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| Series: | Hepatology Communications |
| Online Access: | https://doi.org/10.1002/hep4.1495 |
| _version_ | 1797706726284197888 |
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| author | Francisco Javier Cubero Mohamed Ramadan Mohamed Marius M. Woitok Gang Zhao Maximilian Hatting Yulia A. Nevzorova Chaobo Chen Johannes Haybaeck Alain deBruin Matias A. Avila Mark V. Boekschoten Roger J. Davis Christian Trautwein |
| author_facet | Francisco Javier Cubero Mohamed Ramadan Mohamed Marius M. Woitok Gang Zhao Maximilian Hatting Yulia A. Nevzorova Chaobo Chen Johannes Haybaeck Alain deBruin Matias A. Avila Mark V. Boekschoten Roger J. Davis Christian Trautwein |
| author_sort | Francisco Javier Cubero |
| collection | DOAJ |
| 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 NEMOΔhepa/JNK1Δhepa 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 NEMOΔhepa mice but in contrast caused massive proliferation of the biliary ducts. Indeed, Jnk1/2 deficiency in hepatocytes of NEMOΔhepa (NEMOΔhepa/JNKΔhepa) animals caused elevated fibrosis, increased apoptosis, increased compensatory proliferation, and elevated inflammatory cytokines expression but reduced HCC. Furthermore, siJnk2 treatment in NEMOΔhepa/JNK1Δhepa mice recapitulated the phenotype of NEMOΔhepa/JNKΔhepa mice. Next, we sought to investigate the impact of molecular pathways in response to compound JNK deficiency in NEMOΔhepa mice. We found that NEMOΔhepa/JNKΔhepa 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 NEMOΔhepa/JNKΔhepa 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. |
| first_indexed | 2024-03-12T05:56:36Z |
| format | Article |
| id | doaj.art-828cc4c1d11a436db79ad5999a83b56a |
| institution | Directory Open Access Journal |
| issn | 2471-254X |
| language | English |
| last_indexed | 2024-03-12T05:56:36Z |
| publishDate | 2020-06-01 |
| publisher | Wolters Kluwer Health/LWW |
| record_format | Article |
| series | Hepatology Communications |
| spelling | doaj.art-828cc4c1d11a436db79ad5999a83b56a2023-09-03T04:33:09ZengWolters Kluwer Health/LWWHepatology Communications2471-254X2020-06-014683485110.1002/hep4.1495Loss of c‐Jun N‐terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling CholangiocarcinomaFrancisco Javier Cubero0Mohamed Ramadan Mohamed1Marius M. Woitok2Gang Zhao3Maximilian Hatting4Yulia A. Nevzorova5Chaobo Chen6Johannes Haybaeck7Alain deBruin8Matias A. Avila9Mark V. Boekschoten10Roger J. Davis11Christian Trautwein12Department of Internal Medicine III University Hospital RWTH Aachen Aachen GermanyDepartment of Internal Medicine III University Hospital RWTH Aachen Aachen GermanyDepartment of Internal Medicine III University Hospital RWTH Aachen Aachen GermanyDepartment of Internal Medicine III University Hospital RWTH Aachen Aachen GermanyDepartment of Internal Medicine III University Hospital RWTH Aachen Aachen GermanyDepartment of Internal Medicine III University Hospital RWTH Aachen Aachen GermanyDepartment of Immunology, Ophthalmology, and ENT Complutense University School of Medicine Madrid SpainDepartment of Pathology Otto‐von‐Guericke University Magdeburg GermanyDepartment of Pathobiology Faculty of Veterinary Medicine Dutch Molecular Pathology Center Utrecht University Utrecht the NetherlandsInstituto de Investigación Sanitaria de Navarra Pamplona SpainNutrition, Metabolism, and Genomics Group Division of Human Nutrition Wageningen University Wageningen the NetherlandsHoward Hughes Medical Institute University of Massachusetts Medical School Worcester MADepartment of Internal Medicine III University Hospital RWTH Aachen Aachen GermanyTargeted 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 NEMOΔhepa/JNK1Δhepa 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 NEMOΔhepa mice but in contrast caused massive proliferation of the biliary ducts. Indeed, Jnk1/2 deficiency in hepatocytes of NEMOΔhepa (NEMOΔhepa/JNKΔhepa) animals caused elevated fibrosis, increased apoptosis, increased compensatory proliferation, and elevated inflammatory cytokines expression but reduced HCC. Furthermore, siJnk2 treatment in NEMOΔhepa/JNK1Δhepa mice recapitulated the phenotype of NEMOΔhepa/JNKΔhepa mice. Next, we sought to investigate the impact of molecular pathways in response to compound JNK deficiency in NEMOΔhepa mice. We found that NEMOΔhepa/JNKΔhepa 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 NEMOΔhepa/JNKΔhepa 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.https://doi.org/10.1002/hep4.1495 |
| spellingShingle | Francisco Javier Cubero Mohamed Ramadan Mohamed Marius M. Woitok Gang Zhao Maximilian Hatting Yulia A. Nevzorova Chaobo Chen Johannes Haybaeck Alain deBruin Matias A. Avila Mark V. Boekschoten Roger J. Davis Christian Trautwein Loss of c‐Jun N‐terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma Hepatology Communications |
| 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 |
| url | https://doi.org/10.1002/hep4.1495 |
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