Notch signalling beyond liver development: emerging concepts in liver repair and oncogenesis

Abstract

Notch signalling is an evolutionarily conserved intercellular pathway involved in many aspects of development and tissue renewal in several organs. The importance of Notch signalling in liver development and morphogenesis is well established. However, the post-natal role of Notch in liver repair/regeneration is only now beginning to be unveiled. Despite the simplicity of the pathway activation, a fine spatial-temporal regulation of Notch signalling is required to avoid pathologic effects. This review highlights recent advances in the field indicating that Notch signalling is involved in the reparative morphogenesis of the biliary tree and in liver carcinogenesis. Defective Notch signalling leads to impaired ability of the liver to repair liver damage, while excessive activation may be involved in liver cancer. Even though much remains to be understood about these mechanisms, including the cross-talk between Notch signalling and other liver morphogens, current evidence suggests that the modulation of the Notch pathway may represent a therapeutic target in chronic liver disease.

Keywords: AGS; Alagille syndrome; CCA; CSC; HCC; HNF; HPC; IGF2; IHBD; Jag-1; Jagged-1; N1ICD; N2ICD; NICD; NOS2; Notch intracellular domain; Notch-1 intracellular domain; Notch-2 intracellular domain; RBP-Jκ; Sox-9; T-ALL; T-cell acute lymphoblastic leukaemia; cancer stem cell; cholangiocarcinoma; hepatic progenitor cell; hepatocellular carcinoma; hepatocyte nuclear factor; inducible nitric oxide synthase; insulin-like-growth factor 2; intrahepatic bile duct; recombination signal binding protein immunoglobulin kappa J; sex determining region Y-box 9.