Notch Signaling in Hepatocellular Carcinoma: Guilty in Association!

Mario Strazzabosco,Luca Fabris

doi:10.1053/j.gastro.2012.10.025

Abstract

Notch signaling is a complex, highly conserved mechanism, originally discovered as critical regulator of cell fate determination during development in several tissues and organs.1,2 Activation of Notch may stimulate cells either to undergo a phenotypic switch or to maintain the original cell phenotype by preventing further differentiation,3 Notch is also involved in establishing organ-specific stem cell niches necessary for epithelial tissue homeostasis.3,4 The Notch system encompasses 4 genes encoding for different membrane receptors (Notch 1, 2, 3, and 4), which are activated by their binding to 5 ligands (Jagged-1, Jagged-2, and Delta-like 1, 3, and 4).4 Cell-to-cell contact is a prerequisite for the activation of Notch signaling.3,4 Whereas Notch receptors are expressed by the “receiver” cell, ligands are expressed by the “transmitter” cell. This interaction leads to the proteolytic cleavage and subsequent nuclear translocation of the intracellular domain of Notch receptors (NICD). Once migrated into the nucleus, NICD associates with the nuclear protein of the RBP-Jκ family and transcriptionally activates several other transcriptional activators or repressors that act as critical regulators of cell differentiation, apoptosis, and proliferation4 (see drawing on the left side of Figure 1). NICD is then rapidly deactivated by phosphorylation and by proteosomal degradation. The signal is maintained through ligand-induced proteolytic supply of new NICD.

Highlights

LUCA FABRIS Department of Clinical Medicine University of Milan-Bicocca Milan, Italy and Department of Surgery, Oncology and Gastroenterology University of Padova Padova, Italy Division of Gastroenterology Regional Hospital Treviso Treviso, Italy
In Alagille syndrome, a genetic condition of defective Notch signaling, paucity of bile ducts is associated with impaired biliary differentiation of hepatic progenitor cells (HPC), suggesting that Notch may act as an important modulator of liver repair in adult life.[7]
NICD1 in embryonic hepatoblasts, a latency time of >6 months was observed before the development of hepatocellular carcinoma (HCC), indicating the requirement of additional hits to induce cell transformation, a behavior shown by many oncogenes.[10]

Summary

Introduction

An oncogenic role for Notch signaling in human cancer was first demonstrated in T-cell acute lymphoblastic leukemia, where gain-of-function mutations in the NOTCH1 gene induced an increased stability of NICD1, resulting in the constitutional activation of the The same authors showed that up-regulation of p53 induced by Notch[1] sensitized HCC cells to tumor necrosis factor-related apoptosis-inducing ligand– induced apoptosis.[15] in mouse models of HCC generated by genetic inactivation of the retinoblastoma pathway, activation of the Notch signaling reduced HCC cell proliferation and tumor growth.[16] Notably, in the same study, dataset analysis of HCC patients showed that higher expression levels of NOTCH1 genes were associated with better survival.

Results

Conclusion