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.

Jagged 1 is a major Notch ligand along cholangiocarcinoma development in mice and humans / Che, L.; Fan, B.; Pilo, Maria Giulia; Xu, Z.; Liu, Yisu; Cigliano, Antonio; Cossu, Antonio; Palmieri, Giovanni; Pascale, Rosa Maria; Porcu, Alberto; Vidili, Gianpaolo; Serra, Marina; Dombrowski, F.; Ribback, S.; Calvisi, Diego Francesco; Chen, X.. - In: ONCOGENESIS. - ISSN 2157-9024. - 5:12(2016), pp. e274-in press. [10.1038/oncsis.2016.73]

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

PILO, Maria Giulia
Membro del Collaboration Group
;
LIU, Yisu
Membro del Collaboration Group
;
CIGLIANO, Antonio
Membro del Collaboration Group
;
COSSU, Antonio
Membro del Collaboration Group
;
PALMIERI, Giovanni
Membro del Collaboration Group
;
PASCALE, Rosa Maria
Membro del Collaboration Group
;
PORCU, Alberto
Membro del Collaboration Group
;
VIDILI, Gianpaolo
Membro del Collaboration Group
;
SERRA, Marina
Membro del Collaboration Group
;
CALVISI, Diego Francesco
;
2016

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.
Jagged 1 is a major Notch ligand along cholangiocarcinoma development in mice and humans / Che, L.; Fan, B.; Pilo, Maria Giulia; Xu, Z.; Liu, Yisu; Cigliano, Antonio; Cossu, Antonio; Palmieri, Giovanni; Pascale, Rosa Maria; Porcu, Alberto; Vidili, Gianpaolo; Serra, Marina; Dombrowski, F.; Ribback, S.; Calvisi, Diego Francesco; Chen, X.. - In: ONCOGENESIS. - ISSN 2157-9024. - 5:12(2016), pp. e274-in press. [10.1038/oncsis.2016.73]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11388/178234
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