Intracellular signaling and hepatocellular carcinoma

Abstract

Liver cancer is the fifth most common cancer and the third most common cause of cancer related death in the world. The recent development of new techniques for the investigations of global change in the gene expression, signaling pathways and wide genome binding has provided novel information for the mechanisms underlying liver cancer progression. Although these studies identified gene expression signatures in hepatocelluar carcinoma, the early steps of the development of hepatocellular carcinomas (HCC) are not well understood. The development of HCC is a multistep process which includes the progressive alterations of gene expression leading to the increased proliferation and to liver cancer. This review summarizes recent progress in the identification of the key steps of the development of HCC with the focus on early events of carcinogenesis and on the role of translational and epigenetic alterations in the development of HCC. Quiescent stage of the liver is supported by several tumor suppressor proteins including p53, Rb and C/EBPα. Studies with chemical models of liver carcinogenesis and with human HCC have shown that the elevation of gankyrin is responsible for the elimination of these three proteins at early steps of carcinogenesis. Later stages of progression of the liver cancer are associated with alterations in many signaling pathways including translation which leads to epigenetic silencing/activation of many genes. Particularly, recent reports suggest a critical role of histone deacetylase 1, HDAC1, in the development of HCC through the interactions with transcription factors such as C/EBP family proteins.

Disease Progression from Chronic Hepatitis C to Cirrhosis and Hepatocellular Carcinoma is Associated with Increasing DNA Promoter Methylation

“…Hepatocellular carcinoma (HCC) is one of the most common malignancies and the third leading cause of cancer death in the world (Iakova et al, 2011). Of the total new cancer cases reported each year, HCC represents 7.9% in men and 6.5% in women (Ferlay et al, 2010).…”

Age-associated Change of C/EBP Family Proteins Causes Severe Liver Injury and Acceleration of Liver Proliferation after CCl4 Treatments

“…Two members of C/EBP family, C/EBP␣ and C/EBP␤, are expressed at high levels in the liver and are involved in the epigenetic control of liver proliferation and steatosis by interacting with p300 and HDAC1 (13)(14)(15). Studies with young and old mice suggested that the phosphorylation of C/EBP␣ at S193 is the major pathway of regulation of interactions of C/EBP␣ with HDAC1 (14).…”

Exogenous hydrogen sulfide promotes hepatocellular carcinoma cell growth by activating the STAT3-COX-2 signaling pathway

“…First, PLC/PRF/5 cells were plated onto 35-mm dishes at a density of 1x10 6 Transwell migration assay. PLC/PRF/5 cells were seeded in 96-well plates at a density of 1x10 4 cells/ml, incubated at 37˚C and added to the upper chamber of a Transwell membrane (Transwell Permeable Support with a 5.0-µm polycarbonate membrane, 6.5-mm insert and 24-well plate; Costar; Corning Life Sciences, Tewksbury, MA, USA).…”

“…Furthermore, the 5-year survival rate worldwide of HCC is still <5%, as a result of its high rate of recurrence and metastasis (5). HCC tumorigenesis is a complex Exogenous hydrogen sulfide promotes hepatocellular carcinoma cell growth by activating the STAT3-COX-2 signaling pathway multistep process that is closely associated with multiple signaling pathways and genes, and these factors can affect cell survival, proliferation, invasion and metastasis (6,7). The role of hepatitis B virus (HBV) or hepatitis C virus infection has been extensively investigated and considered as one of the reasons in the pathogenesis of HCC (8,9).…”