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Determining Bile Duct Density in the Mouse Liver
Published on: April 30, 2019
Jagged 1 is a major Notch ligand along cholangiocarcinoma development in mice and humans
1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.
Abstract:
Intrahepatic cholangiocarcinoma (ICC) is a rare yet deadly malignancy with limited treatment options. Activation of the Notch signalling cascade has been implicated in cholangiocarcinogenesis. However, while several studies focused on the Notch receptors required for ICC development, little is known about the upstream inducers responsible for their activation. Here, we show that the Jagged 1 (Jag1) ligand is almost ubiquitously upregulated in human ICC samples when compared with corresponding non-tumorous counterparts. Furthermore, we found that while overexpression of Jag1 alone does not lead to liver tumour development, overexpression of Jag1 synergizes with activated AKT signalling to promote liver carcinogenesis in AKT/Jag1 mice. Histologically, tumours consisted exclusively of ICC, with hepatocellular tumours not occurring in AKT/Jag1 mice. Furthermore, tumours from AKT/Jag1 mice exhibited extensive desmoplastic reaction, an important feature of human ICC. At the molecular level, we found that both AKT/mTOR and Notch cascades are activated in AKT/Jag1 ICC tissues, and that the Notch signalling is necessary for ICC development in AKT/Jag1 mice. In human ICC cell lines, silencing of Jag1 via specific small interfering RNA reduces proliferation and increases apoptosis. Finally, combined inhibition of AKT and Notch pathways is highly detrimental for the in vitro growth of ICC cell lines. In summary, our study demonstrates that Jag1 is an important upstream inducer of the Notch signalling in human and mouse ICC. Targeting Jag1 might represent a novel therapeutic strategy for the treatment of this deadly disease.
Insights
Jagged 1 (Jag1) ligand is upregulated in intrahepatic cholangiocarcinoma (ICC). Jag1, combined with AKT signaling, promotes ICC development, suggesting Jag1 as a novel therapeutic target for this deadly liver cancer.
Area of Science:
- Oncology
- Molecular Biology
- Hepatology
Background:
- Intrahepatic cholangiocarcinoma (ICC) is a rare and aggressive liver cancer with limited therapeutic options.
- The Notch signaling pathway is implicated in ICC development, but upstream activators remain poorly understood.
- Identifying upstream inducers of Notch signaling is crucial for developing targeted therapies for ICC.
Purpose of the Study:
- To investigate the role of Jagged 1 (Jag1) as an upstream inducer of Notch signaling in intrahepatic cholangiocarcinoma.
- To determine the synergistic effect of Jag1 and activated AKT signaling in promoting ICC development.
- To evaluate Jag1 as a potential therapeutic target for ICC.
Main Methods:
- Analysis of Jag1 expression in human ICC samples.
- Generation and analysis of AKT/Jag1 transgenic mouse models for liver carcinogenesis.
- Molecular analysis of signaling pathways (AKT/mTOR, Notch) in tumor tissues.
- In vitro studies using small interfering RNA (siRNA) to silence Jag1 in ICC cell lines.
- Assessment of combined AKT and Notch pathway inhibition in ICC cell growth.
Main Results:
- Jagged 1 (Jag1) ligand is significantly upregulated in human ICC tissues compared to non-tumorous liver.
- Overexpression of Jag1 synergizes with activated AKT signaling to specifically induce ICC development in mice, characterized by desmoplastic reaction.
- Notch signaling is activated and necessary for ICC development in the AKT/Jag1 mouse model.
- Silencing Jag1 in human ICC cell lines inhibits proliferation and promotes apoptosis.
- Combined inhibition of AKT and Notch pathways severely impairs in vitro ICC cell growth.
Conclusions:
- Jag1 acts as a critical upstream inducer of Notch signaling in both human and mouse ICC.
- The Jag1-Notch axis, in conjunction with AKT signaling, plays a key role in ICC pathogenesis.
- Targeting Jag1 presents a promising novel therapeutic strategy for intrahepatic cholangiocarcinoma.
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