Hepatocellular carcinoma (HCC) is one of the most frequent solid tumors worldwide, with limited treatment options and a dismal prognosis. Thus, there is a strong need to expand the basic and translational research on this deadly disease in order to improve the prognosis of HCC patients. Although the etiologic factors responsible for HCC development have been identified, the molecular pathogenesis of liver cancer remains poorly understood. Recent evidence has shown the frequent downregulation of Ras association domain family (RASSF) proteins both in the early and late stages of hepatocarcinogenesis. Here, we summarize the data available on the pathogenetic role of inactivation of RASSF proteins in liver cancer, the molecular mechanisms responsible for suppression of RASSF proteins in HCC, and the possible clinical implications arising from these discoveries. Altogether, the data indicate that inactivation of the RASSF1A tumor suppressor is ubiquitous in human liver cancer, while downregulation of RASSF2 and RASSF5 proteins is limited to specific HCC subsets. Also, the present findings speak in favour of therapeutic strategies aimed at reexpressing RASSF1A, RASSF2, and RASSF5 genes and/or inactivating the RASSF cellular inhibitors for the treatment of human liver cancer. 1. Introduction Hepatocellular carcinoma (HCC) is one of the most frequent tumors, with 0.25-1 million of newly diagnosed cases each year worldwide [1–3]. HCC burden is not distributed evenly throughout the world. Indeed, more than 80% of HCC cases occur in sub-Saharan Africa and Eastern Asia, whereas a much lower HCC incidence characterizes North and South America, Northern Europe, and Oceania [1–3]. Nonetheless, HCC frequency is rapidly growing in low-rate areas as well. In the latter geographic areas, such a rise in HCC occurrence is the result of a combination of factors, including an increasing incidence of cirrhosis caused by alcohol intake, hepatitis C virus (HCV) and hepatitis B (HBV) chronic infection, as well as a general improvement in survival among cirrhosis patients, who are then at risk of developing HCC [1–3]. Furthermore, the rapidly growing number of cryptogenic cirrhosis and HCC cases might be due to a severe form of nonalcoholic fatty liver disease, namely, the nonalcoholic steatohepatitis (NASH) [2]. HCC is a rapidly lethal disease, with an average life expectancy of about 6 months from the time of the diagnosis [1–3]. Like most other solid tumors, surgery plays a fundamental role in its treatment. Surgical resection, local ablation therapies, and liver
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