Targeting Hepatocellular Carcinoma: What did we Discover so Far?

Abstract

Hepatocellular carcinoma (HCC) is increasingly considered an issue of global importance. Its rates of incidence and mortality have been markedly increasing over the last decades. Among risk factors, some should be highlighted, namely the infections by hepatitis B and C virus, as well as clinical cases of cirrhosis. HCC is characterized as asymptomatic disease in the initial stages which most often leads to a late diagnosis. At molecular and genetic level HCC represents a highly complex tumor entity, including a wide variety of mutations, thus accounting for different mechanisms of resistance towards therapeutic approaches. In particular, mutations of the TP53 gene, as well as a deregulation between the expression of pro- and anti-apoptotic proteins of the BCL-2 family are observed. Regarding treatment modalities, surgical procedures offer the best chance of cure, however, due to a late diagnosis, most of concerned patients cannot be subjected to them. Chemotherapy and radiotherapy are also ineffective, and currently, the treatment with sorafenib is the most commonly used systemic therapy although it can only increase the patient survival for some months. In this sense, a quick and accurate investigation is of utmost importance in order to develop ways of early diagnosis as well as new therapies for HCC.

Keywords: Hepatocellular carcinoma; P53; molecular biology.

Figure 1.

Schematic representation of the main molecular and genetic alterations present in hepatocellular carcinoms (HCC). In many cases of HCC are present mutations in the TP53 gene which induces changes in the expression of the corresponding protein P53. It is also quite common to observe an over expression of vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF), as well as a RAF-MEK-ERK/MAPK signaling pathway activation.

Figure 2.

Schematic representation of some of the major effects that the P53 has on proteins involved in cell death pathways. It is noted the occurrence of a feedback mechanism between P53 and MDM2. It is also observed that the P53 regulates the expression of P21, cyclin G and 14th-3-3σ well as induces a BAX over-expression.

Figure 3.

Several molecular targets of sorafenib. Sorafenib inhibits the autophosphorylation of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3 and platelet-derived growth factor receptor (PDGFR)-β, as well as prevents RAF activation. Inhibition of RAF is associated with downregulation of some downstream signaling pathways and other molecular pathways leading to apoptosis.