title: Jagged 1 is a major Notch ligand along cholangiocarcinoma development in mice and humans.
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.
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.|Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Che
authors.affiliation: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China.|Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Fan
authors.affiliation: Institute of Pathology, University of Greifswald, Greifswald, Germany.
authors.forename: M G
authors.initials: MG
authors.lastname: Pilo
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.|Department of Gastroenterology, Guizhou Provincial People's Hospital, The Affiliated People's Hospital of Guizhou Medical University, Guiyang, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Gastroenterology, 307 Hospital of PLA, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Pathology, University of Greifswald, Greifswald, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Cigliano
authors.affiliation: Unit of Pathology, Azienda Ospedaliero Universitaria Sassari, Sassari, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Cossu
authors.affiliation: Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Palmieri
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: R M
authors.initials: RM
authors.lastname: Pascale
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Porcu
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Vidili
authors.affiliation: Institute of Pathology, University of Greifswald, Greifswald, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Serra
authors.affiliation: Institute of Pathology, University of Greifswald, Greifswald, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Dombrowski
authors.affiliation: Institute of Pathology, University of Greifswald, Greifswald, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Ribback
authors.affiliation: Institute of Pathology, University of Greifswald, Greifswald, Germany.|Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: D F
authors.initials: DF
authors.lastname: Calvisi
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Chen