Elimination of Tumor Suppressor Proteins during Liver Carcinogenesis

Nikolai A. Timchenko* and Kyle Lewis

Elimination of Tumor Suppressor Proteins during Liver Carcinogenesis. 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.

One of these additional pathways includes activation of a small subunit of the proteasome, Gankyrin. Gankyrin is
dramatically increased in human hepatocellular carcinoma 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 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/EBPαdependent 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. The development of hepatocellular carcinoma has a long history of affecting mainly adults. In the majority of cases, HCC develops in patients which have chronic liver diseases and or are under chemical treatments. These chronic diseases affect many signaling pathways leading to liver cancer.

Cancer Stud Mol Med Open J. 2014; 1(1): 27-38. doi: 10.17140/CSMMOJ-1-104