Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most frequent tumors, with 0.25-1 million of newly diagnosed cases each year worldwide [1,2,3]
In most investigations, reduced levels of RASSF1A were found to be ubiquitous in HCC regardless of the etiologic factors associated with tumor development, strongly suggesting that universal inactivation of RASSF1A in liver cancer is required for hepatocarcinogenesis [6, 16,17,18,19,20,21,22]
As concerns the relationship between RASSF1A promoter hypermethylation and the clinicopathological parameters of HCC patients, it has been shown that RASSF1A epigenetic silencing is significantly associated with the levels of DNA adducts generated by aflatoxin B1 (AFB1), a mycotoxin with hepatocarcinogenic potential produced by the fungus Aspergillus Flavus [16]
Summary
Hepatocellular carcinoma (HCC) is one of the most frequent tumors, with 0.25-1 million of newly diagnosed cases each year worldwide [1,2,3]. Local ablation therapies, and liver transplantation are regarded as potentially curative treatment modalities for HCC These therapeutic approaches can be applied only to a limited number of HCC patients since the diagnosis is most often done in the late stages of the disease [1,2,3]. Molecular Biology International patients is limited to about three months, implying that Sorafenib alone cannot substantially modify the prognosis of patients with advanced HCC [4] This emphasizes the need to investigate the contribution of different signaling pathways to tumor development and progression in human HCC in order to identify novel prognostic markers and molecular targets for its early diagnosis, chemoprevention, and treatment.
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