Notch Signaling in Hepatocellular Carcinoma: Guilty in Association! Mario Strazzabosco  Gastroenterology  Volume 143, Issue 6, Pages 1430-1434 (December 2012) DOI: 10.1053/j.gastro.2012.10.025 Copyright © 2012 AGA Institute Terms and Conditions

Figure 1 Effects of Notch activation in hepatic progenitor cells in normal and experimental conditions. Activation of Notch signaling requires the close contact between Notch-expressing “receiving” cells and Jag/Dll-expressing “transmitting” cells. This interaction leads to the proteolytic cleavage and subsequent nuclear translocation of the NICD. By associating with the nuclear protein of the RBP-Jκ family, NICD transcriptionally activates several Notch target genes acting as critical regulators of cell differentiation and proliferation. In normal conditions, transient Notch activation in hepatic progenitor cells enables them to differentiate into cholangiocytes by inducing the expression of transcription factors critical for biliary lineage (including Hes-1, HNF1β, and Sox9). In experimental conditions, constitutional activation of Notch generated by inducing the AFP-Cre–mediated overexpression of NICD1 in embryonic hepatic progenitor cells, leads to the generation of HCC showing some features of CSC activation. Sox9 and IGF2 are critical modulators of NICD1-induced liver carcinogenesis. Signatures of Notch activation can be found in about 30% of patients with HCC. In these patients, the Notch signature co-clustered with specific molecular subgroups of HCC, mainly including the “proliferation class” and an “CSC-driven” HCC. In addition, a “CCA-like” HCC and a “TGFβ-driven” HCC are also associated with the Notch signature. CCA, cholangiocarcinoma; CSC, cancer stem cell; DLL, delta-like; HCC, hepatocellular carcinoma; HPC, hepatic progenitor cell; JAG, Jagged; NICD, Notch intracellular domain. Gastroenterology 2012 143, 1430-1434DOI: (10.1053/j.gastro.2012.10.025) Copyright © 2012 AGA Institute Terms and Conditions