It is estimated that 170 million people are seropositive for anti-HCV, of which 127 million are chronically infected [1]. After acute viral infection, over half of the patients develop chronic HCV, which causes more fre quent cirrhosis than chronic HBV (70 versus 50%) [8].

Hepatitis C virus is a single-stranded RNA virus that does not integrate into the host genome [1]. Hostviral protein interactions are the major pathways of hepatocar cinogenesis. The HCV genome is translated into a poly protein which is processed into at least 10 polypeptides, including structural (Core, E1, E2, and p7) and non struc tural (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) pro teins [14].

Analysis of HCV-associated HCC tumor tissues revealed a high incidence of chromosome instability. The overexpression of the NS5A protein leads to an unsched uled delay in mitotic exit and to multi-polar spindles [15]. The expression of this protein may lead to a reduced syn thesis (S) phase and an increase in the postsynthetic gap 2/mitotic (G2/M) phase [16]. The NS5B protein also trig gers cell cycle arrest in the G2 phase, and its functional interaction with NS5A suggests a possible cooperation of these proteins in HCV-induced mitotic impairments [15]. The NS5A expression may alter the levels of intracellular calcium and reactive oxygen species which activate STAT3 and NFêB [16]. The latter induces the expression of anti-apoptotic factors, such as inhibitors of apoptosis (IAP) and Bcl-2 in chronic HCV patients [15]. The NS5A protein can protect against TNFá-mediated apoptotic cell death, interact with the newly identified tumor suppressor bridging integrator 1 (Bin1), and inhibit apoptosis. The NS5A protein also inhibits p53-mediated apoptosis by sequestering p53 in cytoplasm and forms a complex with PI3K in the epidermal growth factor (EGF) signaling path way, enhances the PI3K-AKT pathway and contributes to cell survival in virus-infected cells [16].

The NS2 protein acts as an apoptosis inhibitor by interaction with the liver-specific pro-apoptotic protein cell death-inducing DFFA-like affector B (CIDE-B). The expression of NS2 may inhibit the human TNFá promoter and the expression of cyclin A that leads to cell cycle arrest in the S phase [14].

Hepatitis C virus core protein is found in various sub cellular compartments, including cytosol, endoplasmic reticulum/Golgi apparatus, mitochondria, and nuclei [17]. It has transcriptional regulating functions on diverse cellu lar genes including activation of the c-myc promoter and suppression of the c-fos oncogene promoter [18]. It could promote both apoptosis and cell proliferation through its interaction with p53 [3]. The core protein can modulate the expression of the cyclin-dependent inhibitor p21^Waf1, and an increased level of p21 corresponds to a decrease in CDK2 kinase activity with hepatocyte arrest in the gap 0/gap 1 (G0/G1) phase of the cell cycle. Cyclin E is ele vated in cells that express the core protein. The decreased expression of the hepatic pro-growth factors, hepatocyte growth factor (HGFR) and á-fetoprotein (AFP) in HepG2 cells shows that the Core protein expression suppresses cell proliferation [18]. The core protein stimulates HCC cell proliferation at least partly through upregulation of Wnt-1 at the transcriptional level [3]. The core protein expression can lead to increased expression of the inhibitor of kappa B (IêB) á subunit of the IêB complex which enhances inactivation of the NFêB transcription complex [18]. The core protein may contribute to transfor mation via mechanisms that involve oxidative stress which stimulates JAK/STAT signaling [9]. It also upregulates STAT3 and activates downstream signaling molecule Bcl-2-like 1 protein (Bcl-xL) [17]. It can inhibit multiple activators of apoptosis, including TNF receptor superfamily member 6 (Fas) and TNFá, possibly through constitutive activation of a MAPK/ERK signaling cascade [1]. It may downregulate the expression of the suppressor of cytokine signaling (SOCS-1) gene, and thus contribute to the patho genesis in HCV infection including hepatocarcinogenesis [17].