Program in Molecular Medicine; Davis Lab
Cancer Biology | Cell Biology | Cells | Cellular and Molecular Physiology | Digestive System Diseases | Enzymes and Coenzymes | Hepatology | Neoplasms | Physiological Processes
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 (Deltahepa)) 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(Deltahepa)/JNK1(Deltahepa) 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(Deltahepa) mice but in contrast caused massive proliferation of the biliary ducts. Indeed, Jnk1/2 deficiency in hepatocytes of NEMO(Deltahepa) (NEMO(Deltahepa)/JNK(Deltahepa)) animals caused elevated fibrosis, increased apoptosis, increased compensatory proliferation, and elevated inflammatory cytokines expression but reduced HCC. Furthermore, siJnk2 treatment in NEMO(Deltahepa)/JNK1(Deltahepa) mice recapitulated the phenotype of NEMO(Deltahepa)/JNK(Deltahepa) mice. Next, we sought to investigate the impact of molecular pathways in response to compound JNK deficiency in NEMO(Deltahepa) mice. We found that NEMO(Deltahepa)/JNK(Deltahepa) 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(Deltahepa)/JNK(Deltahepa) 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.
c‐Jun N‐terminal kinases (JNKs), cholangiocytes, cholangiocarcinogenesis
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© 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 Creative Commons Attribution‐NonCommercial‐NoDerivs 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.
DOI of Published Version
Cubero FJ, Mohamed MR, Woitok MM, Zhao G, Hatting M, Nevzorova YA, Chen C, Haybaeck J, de Bruin A, Avila MA, Boekschoten MV, Davis RJ, Trautwein C. Loss of c-Jun N-terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma. Hepatol Commun. 2020 Apr 16;4(6):834-851. doi: 10.1002/hep4.1495. PMID: 32490320; PMCID: PMC7262317. Link to article on publisher's site
Cubero FJ, Mohamed MR, Woitok MM, Zhao G, Hatting M, Nevzorova YA, Chen C, Haybaeck J, de Bruin A, Avila MA, Boekschoten MV, Davis RJ, Trautwein C. (2020). Loss of c-Jun N-terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1002/hep4.1495. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1721
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