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8.2.5 HCV Induces Oxidative Stress
Altered redox balance is one of the common hallmarks of tumors. Cancer cells
exhibit high reactive oxygen species (ROS), which in turn is compensated by an
increased antioxidant ability [ 57 ]. High ROS can induce DNA damage and genomic
instability, which then further active inflammatory response and reprogramming
metabolism of cancer cells [ 58 , 59 ]. HCV infection is frequently associated with
oxidative stress [ 60 – 62 ]. In chronically HCV-infected patients, there is frequently
elevated iron in serum or in the liver, and the iron overload may play an important
role in hepatic oxidative stress [ 62 ]. Upon overexpression, HCV core, E1, NS3, and
NS5A are potent inducers of oxidative stress [ 63 ]. In a HCV core-transgenic mouse,
the core protein induces hepatocellular carcinoma probably through altering the
oxidant/antioxidant state [ 64 , 65 ].
Oxidative stress or oxidative stress-generated products activate quiescent stel-late cells and cultural fibroblasts to increase production of collagen type I, contrib-
uting to hepatic fibrosis. Free radicals and malondialdehyde, a product of lipid
peroxidation, activate stellate cells [ 66 ]. Ascorbic acid induces lipid peroxidation
and reactive aldehydes to stimulate collagen gene expression in cultured fibroblasts
[ 67 ]. Generation of reactive oxygen species (ROS) may activate inflammation
engaging the NLRP3 inflammasome [ 68 ] to contribute to fibrosis as discussed
above.
8.2.6 Hepatic Stellate Cells (HSCs) and Fibrosis
Cross talk of parenchymal with nonparenchymal cells, along with signaling of
inflammation, provides a permissive microenvironment for transition of prolifera-
tive hepatocytes into hepatocellular carcinoma [ 69 ]. Most HCC patients are associ-
ated with fibrosis. Stromal fibroblasts have a profound influence in cancer initiation
and progression [ 70 ]. Following liver damage, hepatic stellate cells (HSCs) are acti-
vated to become matrix-secreting myofibroblasts, providing the major source of
extracellular matrix (ECM), and may directly influence HCC through effects on the
tumor stroma [ 71 ]. Primary human HSCs and HSC cell lines are not permissive for
HCV entry or replication [ 72 ]. However, hepatoma cells expressing HCV core or
HCV-infected cells activate HSC through a TGF-β-dependent signaling pathway
[ 35 , 55 ]. Reciprocally, when cocultured with HCV-infected cells, HSC secrets
IL-1α to stimulate HCV-infected hepatocytes to express pro-inflammatory cyto-
kines and chemokines, which may contribute to inflammation-mediated, HCV-
related diseases [ 52 ].
Z. Yi and Z. Yuan