Jagged 1 is a major Notch ligand along cholangiocarcinoma development in mice and humans.

R M Pascale,A Porcu,S Ribback,Z Xu,Y Liu,B Fan,A Cigliano,F Dombrowski,M Serra,G Vidili,A Cossu,X Chen,L Che,M G Pilo,D F Calvisi,G Palmieri

doi:10.1038/oncsis.2016.73

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.

Highlights

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver tumour, and is characterized by an extremely unfavourable prognosis.[1,2] In the past decades, the incidence of ICC has been increasing by threefold to fivefold worldwide, including the USA.[3,4] Treatment options for ICC are very limited.[5,6] While surgical resection can be applied to a minority of patients,[7] chemotherapy is the standard care for advanced ICC
We show that Jag[1] is overexpressed in human ICC specimens and regulates the in vitro growth of human ICC cell lines via the Notch signalling
Equivalent levels of Jag[1] immunoreactivity in ICC and corresponding non-neoplastic livers were detected in the remaining samples (Figure 1a, lower panel)

Summary

Introduction

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver tumour, and is characterized by an extremely unfavourable prognosis.[1,2] In the past decades, the incidence of ICC has been increasing by threefold to fivefold worldwide, including the USA.[3,4] Treatment options for ICC are very limited.[5,6] While surgical resection can be applied to a minority of patients,[7] chemotherapy is the standard care for advanced ICC. It has only very limited efficacy.[5]. The contribution of these genetic and signalling events in cholangiocarcinogenesis requires further validation using in vitro and in vivo approaches

Methods

Results

Conclusion