Elimination of Tumor Suppressor Proteins during Liver Carcinogenesis

Abstract

Liver cancer is one of the most lethal cancers. Quiescent liver expresses up to 20
tumor suppressor proteins including Rb, p53, CCAAT-Enhancer-Binding Protein (C/EBP)α,
Hepatocyte Nuclear Factor (HNF4)α and p16 and it is well protected from development of
liver cancer. However, the negative control of liver proliferation by these factors and other
tumor suppressor genes is eliminated in liver cancer. Studies of liver regeneration after surgery
and injury have provided fundamental mechanisms on how liver neutralizes tumor suppressor
proteins for the time of regeneration; however, studies of liver cancer in animal models and in
human samples showed several additional pathways of this neutralization. One of these additional
pathways includes activation of a small subunit of the proteasome, Gankyrin. Gankyrin is
dramatically increased in human hepatocellular carcinoma (HCC) and in animal models of carcinogenesis.
Once activated Gankyrin triggers degradation of main tumor suppressor proteins
during development of liver cancer using slightly different mechanisms. Recent studies identified
mechanisms which repress Gankyrin in quiescent livers and mechanisms of activation of
Gankyrin in liver cancer. These mechanisms involve a communication between Farnesoid X
Receptor (FXR) signaling and chromatin remodelling proteins mediated by members of C/EBP
family. It has been recently shown that C/EBPα plays a critical role in this network and that the
activation of C/EBPα in cirrhotic livers with HCC inhibits cancer progression. This C/EBPα-
dependent inhibition of liver cancer involves activation of a majority of tumor suppressor genes
and repression of tumor initiating pathways such as β-catenin and c-myc. These recent findings
provide a background for FXR-based and C/EBPα-based approaches to treat liver cancer.