Rs, which bind promoters of many genes, including growth factor and cytokine genes, which are important in promoting growth and preventing the apoptosis ofwww.impactjournals.com/oncotargetmultiple cell types [38-40]. Deregulation of the Ras/Raf/MEK/ERK BX795 site pathway plays a key role in the pathogenesis of several human cancers [17, 41, 42], including HCC [21, 43-48]. Although mutations of Ras and Raf occur BX795MedChemExpress BX795 infrequently in HCC, a recent study demonstrated that activation of the Ras pathway was observed in 100 of HCC specimens analyzed when compared with non-neoplastic surrounding tissue and normal livers. This increased expression of Ras coincided with the decreased expression of genes which serve to inhibit Ras expression, namely the Rasassociation domain family 1A (RASSF1A) and the novel Ras effector 1A (NORE1A). These genes may be suppressed due to aberrant methylation of their promoters [49]. In addition, activation of the Ras/Raf/MEK/ERK pathway in HCC may be due to the down-regulation of Ras inhibitors Sprouty and Sprouty-related protein with Ena/vasodilator-stimulated phosphoprotein homology-1 domain (Spred-1) and Spred-2 [50, 51]. It has been shown that the expression of Spred-1 and -2 in human HCC tissues is frequently lower than in the adjacent nontumor tissue and inversely correlates with the incidence of tumor invasion and metastasis [51]. Moreover, forced expression of Spred inhibited HCC cell proliferation both in vitro and in vivo, which was associated with reduced ERK activation, suggesting that Spred could be not only a novel prognostic factor but also a new therapeutic target for human HCC [51]. Recently, studies have also shown that down-regulation of Raf kinase inhibitor protein (RKIP) expression is a major factor in the activation of the ERK/MAPK pathway during human liver carcinogenesis [52, 53]. Deregulation of the ERK pathway has clinical importance in HCC. Activation of the ERK signaling pathway predicts poor prognosis in hepatocellular carcinoma [54]. The important role of ERK signaling has also been suggested for HCC progression in obese patients. A possible explanation for an associated risk for obesity and HCC comes from the study of Saxena et al., which for the first time demonstrated that leptin, a key molecule involved in the regulation of energy balance and body weight control, promotes HCC growth and invasiveness through activation of ERK signaling [55]. Other well known risk factors for HCC such as HBV and HCV infection also seem to utilize the Raf/MEK/ERK pathway for the control of hepatocyte survival and viral replication [56, 57]. HBx, one of the four proteins encoded by the HBV genome, has been reported to be involved in liver carcinogenesis, with HBx expression activating the Ras, Raf, MAP kinase signaling cascade [56, 58-60]. Among the HCV components, the core protein has been reported to activate the Ras/Raf/MEK/ERK pathway and thereby might contribute to HCC carcinogenesis [57, 61, 62]. Therefore, these studies suggested the possible use of the Raf/MEK/ERK pathway as a target in therapeuticOncotarget 2012; 3: 236-approaches for the treatment of HCC resulting from HBV and HCV infection. Taken together, these data suggest that the Raf/MEK/ERK pathway may represent an important therapeutic target for the treatment of HCC in patients with differing etiologies that lead to the development of this aggressive tumor. Activation of Ras/Raf/MEK/ERK signaling in HCC may result from up-regulation of IGF [63], ab.Rs, which bind promoters of many genes, including growth factor and cytokine genes, which are important in promoting growth and preventing the apoptosis ofwww.impactjournals.com/oncotargetmultiple cell types [38-40]. Deregulation of the Ras/Raf/MEK/ERK pathway plays a key role in the pathogenesis of several human cancers [17, 41, 42], including HCC [21, 43-48]. Although mutations of Ras and Raf occur infrequently in HCC, a recent study demonstrated that activation of the Ras pathway was observed in 100 of HCC specimens analyzed when compared with non-neoplastic surrounding tissue and normal livers. This increased expression of Ras coincided with the decreased expression of genes which serve to inhibit Ras expression, namely the Rasassociation domain family 1A (RASSF1A) and the novel Ras effector 1A (NORE1A). These genes may be suppressed due to aberrant methylation of their promoters [49]. In addition, activation of the Ras/Raf/MEK/ERK pathway in HCC may be due to the down-regulation of Ras inhibitors Sprouty and Sprouty-related protein with Ena/vasodilator-stimulated phosphoprotein homology-1 domain (Spred-1) and Spred-2 [50, 51]. It has been shown that the expression of Spred-1 and -2 in human HCC tissues is frequently lower than in the adjacent nontumor tissue and inversely correlates with the incidence of tumor invasion and metastasis [51]. Moreover, forced expression of Spred inhibited HCC cell proliferation both in vitro and in vivo, which was associated with reduced ERK activation, suggesting that Spred could be not only a novel prognostic factor but also a new therapeutic target for human HCC [51]. Recently, studies have also shown that down-regulation of Raf kinase inhibitor protein (RKIP) expression is a major factor in the activation of the ERK/MAPK pathway during human liver carcinogenesis [52, 53]. Deregulation of the ERK pathway has clinical importance in HCC. Activation of the ERK signaling pathway predicts poor prognosis in hepatocellular carcinoma [54]. The important role of ERK signaling has also been suggested for HCC progression in obese patients. A possible explanation for an associated risk for obesity and HCC comes from the study of Saxena et al., which for the first time demonstrated that leptin, a key molecule involved in the regulation of energy balance and body weight control, promotes HCC growth and invasiveness through activation of ERK signaling [55]. Other well known risk factors for HCC such as HBV and HCV infection also seem to utilize the Raf/MEK/ERK pathway for the control of hepatocyte survival and viral replication [56, 57]. HBx, one of the four proteins encoded by the HBV genome, has been reported to be involved in liver carcinogenesis, with HBx expression activating the Ras, Raf, MAP kinase signaling cascade [56, 58-60]. Among the HCV components, the core protein has been reported to activate the Ras/Raf/MEK/ERK pathway and thereby might contribute to HCC carcinogenesis [57, 61, 62]. Therefore, these studies suggested the possible use of the Raf/MEK/ERK pathway as a target in therapeuticOncotarget 2012; 3: 236-approaches for the treatment of HCC resulting from HBV and HCV infection. Taken together, these data suggest that the Raf/MEK/ERK pathway may represent an important therapeutic target for the treatment of HCC in patients with differing etiologies that lead to the development of this aggressive tumor. Activation of Ras/Raf/MEK/ERK signaling in HCC may result from up-regulation of IGF [63], ab.