 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Jun 08, 2020 |
| Title |
Hepatocytic c-Jun N-terminal kinases (JNK)-1/2 function determines cell fate during carcinogenesis |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
|
| Summary |
Aberrant biliary hyperproliferation resulting from lack of differentiating signals favoring the maintenance of an immature and proliferative phenotype by biliary epithelial cells are ultimately responsible for ducto/cystogenesis and intrahepatic cholangiocarcinoma (CCA) formation. Mitogen-activated protein kinase (MAPK) signaling is pivotal for CCA-related tumorigenesis. In particular, targeted inhibition of JNK signaling has shown therapeutic potential. However, the cell-type specific role and mechanisms triggered by JNK in liver parenchymal cells during CCA remains largely unknown. Here, we aimed to investigate the relevance of JNK function in hepatocytes in experimental carcinogenesis. JNK signaling in hepatocytes was inhibited by crossing AlbCre-JNK1LoxP/LoxP mice with JNK2-deficient mice to generate Jnk1LoxP/LoxP/Jnk2−/− (JNKΔhepa) mice. JNKΔhepa mice were further interbred with hepatocyte-specific Nemo-knockout mice (NEMOΔhepa), a model of chronic liver inflammation and spontaneous hepatocarcinogenesis, to generate NEMO/JNKΔhepa mice. The impact of JNK deletion on liver damage, cell death, compensatory proliferation, fibrogenesis, and tumor development in NEMOΔhepa mice was determined. Moreover, regulation of essential genes was assessed by RT-PCR, immunoblottings and immunostains. Additionally, JNK2 inhibition, specifically in hepatocytes of NEMOΔhepa/JNK1Δhepa mice, was performed using siRNA (siJnk2) nanodelivery. Finally, active signaling pathways were blocked using specific inhibitors. Compound deletion of JNK1 and JNK2 in hepatocytes diminished hepatocarcinogenesis in both the DEN model of hepatocarcinogenesis and in NEMOΔhepa mice, but, in contrast, caused massive proliferation of the biliary ducts. Indeed, JNK deficiency in hepatocytes of NEMOΔhepa (NEMOΔhepa/JNKΔhepa) animals caused elevated fibrosis, increased apoptosis, increased compensatory proliferation, and elevated inflammatory cytokines expression, but reduced hepatocarcinogenesis. 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 IL-6/Stat3 pathway in addition to EGFR-Raf-MEK-ERK cascade. The functional relevance was tested by administering lapatinib - a dual tyrosine kinase inhibitor (TKI) of ErbB2 and EGFR signaling - to NEMOΔhepa/JNKΔhepa mice. Lapatinib effectively inhibited cystogenesis, improved transaminases and effectively blocked EGFR-Raf-MEK-ERK signaling. Our study defines a novel function of JNK in cell fate as well as hepatocarcinogenesis and opens new therapeutic avenues devised to inhibit pathways of cholangiocarcinogenesis.
|
| |
|
| Overall design |
Livers were isolated from control, NEMO (NEMOΔhepa) single-knockout, NEMO/JNK1Δhepa (NEMOΔhepa/JNK1Δhepa) double-knockout, JNKΔhepa (Jnk1Δhepa/Jnk2Δhepa) double-knockout, and NEMO/JNKΔhepa (NEMOΔhepa/Jnk1Δhepa/Jnk2Δhepa) triple-knockout mice, after some of which were bile duct ligated or treated with DEN, and subjected to gene expression profiling.
|
| |
|
| Contributor(s) |
Cubero FJ, Mohamed MR, Boekschoten MV, Trautwein C |
| Citation(s) |
32490320 |
| |
| Submission date |
Nov 15, 2019 |
| Last update date |
Jun 08, 2020 |
| Contact name |
Guido Hooiveld |
| E-mail(s) |
[email protected]
|
| Organization name |
Wageningen University
|
| Department |
Div. Human Nutrition & Health
|
| Lab |
Nutrition, Metabolism & Genomics Group
|
| Street address |
HELIX, Stippeneng 4
|
| City |
Wageningen |
| ZIP/Postal code |
NL-6708WE |
| Country |
Netherlands |
| |
|
| Platforms (1) |
| GPL11533 |
[MoGene-1_1-st] Affymetrix Mouse Gene 1.1 ST Array [transcript (gene) version] |
|
| Samples (24)
|
| GSM4171615 |
Liver, NEMO/JNKΔhepa triple knockout mouse, replicate 1 |
| GSM4171616 |
Liver, NEMO/JNKΔhepa triple knockout mouse, replicate 2 |
| GSM4171617 |
Liver, NEMO/JNKΔhepa triple knockout mouse, replicate 3 |
| GSM4171618 |
Liver, control mouse treated with DEN, replicate 1 |
| GSM4171619 |
Liver, control mouse treated with DEN, replicate 2 |
| GSM4171620 |
Liver, control mouse treated with DEN, replicate 3 |
| GSM4171621 |
Liver, JNKΔhepa double knockout mouse treated with DEN, replicate 1 |
| GSM4171622 |
Liver, JNKΔhepa double knockout mouse treated with DEN, replicate 2 |
| GSM4171623 |
Liver, JNKΔhepa double knockout mouse treated with DEN, replicate 3 |
| GSM4171624 |
Liver, control mouse, bile duct ligation, replicate 1 |
| GSM4171625 |
Liver, control mouse, bile duct ligation, replicate 2 |
| GSM4171626 |
Liver, control mouse, bile duct ligation, replicate 3 |
| GSM4171627 |
Liver, JNKΔhepa double knockout mouse, bile duct ligation, replicate 1 |
| GSM4171628 |
Liver, JNKΔhepa double knockout mouse, bile duct ligation, replicate 2 |
| GSM4171629 |
Liver, JNKΔhepa double knockout mouse, bile duct ligation, replicate 3 |
| GSM4171630 |
Liver, NEMO knockout mouse, replicate 1 |
| GSM4171631 |
Liver, NEMO knockout mouse, replicate 2 |
| GSM4171632 |
Liver, NEMO knockout mouse, replicate 3 |
| GSM4171633 |
Liver, NEMO/JNK1Δhepa double knockout mouse, replicate 1 |
| GSM4171634 |
Liver, NEMO/JNK1Δhepa double knockout mouse, replicate 2 |
| GSM4171635 |
Liver, NEMO/JNK1Δhepa double knockout mouse, replicate 3 |
|
| Relations |
| BioProject |
PRJNA589901 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE140498_RAW.tar |
103.8 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
|
|
|
|
 |
Less...
More...