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(EMT) plays an important role in early stages of metastasis [ 25 ]. HCV infection
provokes production of transform growth factor beta (TGF-β) that is a potent inducer
of EMT [ 26 , 27 ]. Thus, HCV infection directly affects infected hepatocyte or indi-
rectly shapes intrahepatic microenvironment to prompt development of hepatocel-
lular carcinoma.
8.2.1 HCV Viral Proteins Interfere with Cell Proliferation
and Apoptosis
Oncovirus is commonly not sufficient to drive cancer development, but is neces-
sary for human viral oncogenesis. During many years of persistent infection, viral
oncogenes trigger proliferative and antiapoptotic programs to prompt oncogenesis
[ 22 ]. Numerous studies suggest that HCV proteins trigger proliferative signaling.
By means of overexpression in cultured cells, HCV core and NS5A activate pro-
survival β-catenin and phosphoinositide 3-kinase (PI3K) signaling pathway [ 28 –
31 ]. HCV NS5B induces tumor suppressor protein (pRb) degradation via
ubiquitination of pRb and proteasome-dependent degradation to activate E2F-
responsive promoters and cell proliferation [ 32 , 33 ]. In a transgenic mouse model
expressing the entire HCV open reading frame, HCV NS5A activates Akt to stabi-
lize β-catenin, resulting in activation of the c-Myc promoter and aberrant cell cycle
arrest [ 34 ]. In a HCV core-transgenic mouse model, activated transforming growth
factor beta (TGF-β) may drive the cross talk between hepatocytes and stromal envi-
ronment [ 35 ]. However, infection of a cultured HCV strain JFH1 indicates a slow-
down in proliferation and delayed cell cycle progression and apoptosis [ 36 , 37 ]. In
agreement with this, HCV NS5B interacts with cyclin-dependent kinase
2- interacting protein (CINP) to delay S-phase progression in hepatoma cells [ 38 ].
This discrepancy might be due to the unique of the JFH1 strain. HCV proteins also
modulate apoptosis signaling pathway. HCV proteins such as core, E1, E2, NS2,
NS3, and NS5A interfere with cellular apoptotic signaling pathway (reviewed in
[ 39 , 40 ]). In HCV chronically infected patients, there are detectable apoptotic cells
and caspase activation in the liver that is probably due to immune-mediated liver
injury [ 41 , 42 ].
8.2.2 HCV Infection and Host Genetic Alteration
During hepatocarcinogenesis, accumulative genomic alteration progressively
changes the hepatocellular phenotype and eventually renders the hepatocellular car-
cinoma development [ 43 ]. HCV infection of two B-cell lines induces mutations in
tumor suppressor and proto-oncogenes, which is evidenced in HCV-associated
B-cell lymphomas [ 44 ]. HCV-infected PBMCs also show chromosome gaps with a
Z. Yi and Z. Yuan