In:
Hepatology Communications, Ovid Technologies (Wolters Kluwer Health), Vol. 4, No. 6 ( 2020-06), p. 834-851
Abstract:
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 (si Jnk2 ) 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, si Jnk2 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.
Type of Medium:
Online Resource
ISSN:
2471-254X
,
2471-254X
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2020
detail.hit.zdb_id:
2881134-3
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