HCC is the only malignancy whose occurrence in patients is associated with the appearance of risk factors, such as chronic liver inflammation and cirrhosis[130
]. However, the extensive epidemiological studies performed in the last decades led to the identification of major risk factors of HCC and thereby helped to understand the pathogenesis of HCC[133
]. Although the advances that made in the understanding of HCC pathogenesis, little is known about the molecular mechanisms of this malignancy. The most changes that occur in liver tissues are thought to result from either viral infection or the exposure to hepatotoxic agents leading to significant changes in the cellular signaling pathways and their target genes that are responsible in the regulation of tumor formation. These pathways include Wnt/β-catenin[8
], mitogen-activated protein (MAP) kinases[142
], stress signaling[144
], epidermal growth factor receptor[151
], and JAK/STAT[155
Wnt/β-catenin pathway has been reported to be involved in the regulation of HCC development in response to viral infection including HCV[156
]. Also, the up-regulation of frizzled-7 and dephosphorylation of β-catenin is frequently observed in HCC[157
]. Therefore, the targeted inactivation of Wnt pathway is considered a potential therapeutic target for the prevention or the ablation of HCV-associated HCV. Moreover, the increase of the mutation in β-catenin in HCC patients in response to either HCV infection[161
] or the exposure to aflatoxin[162
], provides evidence for the involvement of Wnt pathway in the regulation of HCV-associated HCC.
The tumor suppressor P53
gene, which can be inactivated by single point mutation[164
], is one of the most studied proteins in the context of tumor development. Although the expression of this protein at normal levels in most tumors, under normal physiological conditions, the level of cellular p53 is low. The alteration of the expression level of p53 in response to either intracellular or extracellular stress signals can lead to significant changes that mostly vary from down regulation to up-regulation[164
]. However, the loss of p53 function as tumor suppressor protein is controlled by defects in p53 signaling.
Retinoblastoma, pRb1 is a major cellular barrier to cancer development that controls cell cycle progression through a mechanism including, the repression of the E2F transcription factor family of proteins[167
]. The phosphorylation of pRb and subsequently G1/S cell cycle transition is mainly correlated with activation of CDKs in different tumor types including, HCC[20
]. In according, HCV core protein-induced acceleration of liver cells was found to be associated with activation of CDKs, inhibition of pRb and the up regulation of E2F1[20
]. In addition, there is strong correlation between the loss of pRB and the inhibition of functional p53 in HCV core expressing cells[21
], as well as in different tumor types including HCC[169
]. The inhibition of CDK inhibitors p16INK4A, p21(WAF1/CIP1), and p27Kip1 in response to frequent mutation, or HCV infection was found to be associated with carcinogenesis of most HCC cases[172
]. Also, the disruption of pRb pathway in various tumor types including, HCC has been reported in several studies[20
], an evidence for the critical role of pRB in carcinogenesis.
Although HCV is a single-stranded RNA virus, and its genome is never integrated into the genome of hepatocytes[175
], and no known oncogenic properties have been reported for its genes, a significant portion of HCV-infected patients with induced cirrhosis has been shown to develop HCC[20
]. Thus, HCV-induced oncogenesis seems to result from the interference of HCV proteins with the intracellular signal transduction processes via
mechanism includes dysregulation of cell cycle control.
Core protein, the most viral protein that is widely reported to interact with several intracellular signal transduction pathways, and thereby orchestrate their function, as oncogenic mediator, by indirect activation of TNF-α receptor[176
], Raf-1 kinase[173
], MAP kinase[36
] and nuclear factor kappa B[180
] pathways. Also, the inhibition of TNF-α-induced apoptosis and the modulation of other cytokines activities during the course of HCV infection may prolong survival of infected hepatocytes, and subsequently leads to the accumulation of genetic damages that mediate the processes of the malignancy[182
Although the direct involvement of HCV core protein in the development of HCC has been demonstrated in transgenic mice[25
], the mechanism(s) whereby HCV core triggers HCC is not completely addressed in human. Apart from HCV core protein, the role of other viral proteins such as, nonstructural proteins NS5A and NS3 in the development of hepatocarcinogenesis is less clear[17
]. A suggested model for the development of HCV-associated HCC is outlined in Figure . Also, the possible mechanisms of HCV-associated HCC are: (1) activation of cellular oncogenes such as, Ras, c-Myc, E2F1 by HCV proteins; (2) inactivation of tumor suppressor genes such as p21, p53, Rb by HCV proteins; and (3) HCV proteins-induced dysregulation of Wnt/β-catenin, MAPK, JAK/STAT, PI3K/Akt, EGF-β, TGF-β pathways.
Figure 3 Molecular mechanisms of hepatitis C virus-mediated hepatocarcinogenesis. Key steps that thought to be involved in the development of hepatitis C virus-associated hepatocellular carcinoma. HCV: Hepatitis C virus; ROS: Reactive oxygen species; IRS: Insulin (more ...)