A Critical Role for Notch Signaling in the Formation of Cholangiocellular Carcinomas
Menée à l'aide d'un modèle murin transgénique, cette étude met en évidence un mécanisme par lequel la voie de signalisation Notch favorise la formation d'un cholangiocarcinome
The incidence of cholangiocellular carcinoma (CCC) is increasing worldwide. Using a transgenic mouse model, we found that expression of the intracellular domain of Notch 1 (NICD) in mouse livers results in the formation of intrahepatic CCCs. These tumors display features of bipotential hepatic progenitor cells, indicating that intrahepatic CCC can originate from this cell type. We show that human and mouse CCCs are characterized by high expression of the cyclin E protein and identified the cyclin E gene as a direct transcriptional target of the Notch signaling pathway. Intriguingly, blocking
γ-secretase activity in human CCC xenotransplants results in downregulation of cyclin E expression, induction of apoptosis, and tumor remission in vivo.
"Notch signaling is frequently dysregulated in human CCCs "Notch is an oncogenic driver of CCC and able to transform hepatic progenitor cells "Notch induces the cyclin E promoter, causing genetic instability by increasing cyclin E expression "Inhibition of Notch signaling may be a treatment option for CCC