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partially overlapped pattern of chromosomal aberrations observed in HCV- associated
hepatocellular carcinomas [ 45 ]. In these cells, HCV-induced chromosomal aberra-
tion is due to the core- and NS3-induced nitric oxide (NO) and reactive oxygen
species (ROS) production [ 45 – 47 ]. In cultured cells, HCV NS3/4A interacts with
the ATM (ataxia-telangiectasia mutated), a cellular protein that plays an essential
role in cellular response to irradiation-induced double-strand DNA breaks, indicat-
ing it may impair efficiency of DNA repair [ 48 ].
8.2.3 HCV Infection and Chronic Inflammation
In chronic infection, HCV activates immune response that fails to clear viral repli-
cation but develops an environment of inflammation and provokes chronic liver
damage-induced regeneration of hepatocyte [ 23 ]. HCV viral components or replica-
tion products act as pathogen-associated molecular pattern (PAMP) to trigger innate
immune response and immune modulatory cytokines [ 49 ]. HCV infection induces
IL-29 and chemokine protein in primary liver cultures [ 50 ]. HCV virion may be
taken up by intrahepatic macrophages, the Kupffer cells, wherein the viral RNA
triggers interleukin-1β (IL-1β) through the NLRP3 inflammasome [ 51 ]. When
cocultured with HCV-infected cells, hepatic stellate cell (HSC) is activated to
prompt HCV-infected hepatocytes to produce pro-inflammatory cytokines, chemo-
kines, and macrophage inflammatory protein 1α (MIP-1α) and MIP-1β [ 52 ].
8.2.4 HCV and Transforming Growth Factor Beta (TGF-β)
In hepatocellular carcinoma progression, the epithelial-to-mesenchymal transition
(EMT) plays an important role in early stages of metastasis [ 25 ]. TGF-β is a potent
inducer of EMT and plays an important role in fibrosis [ 26 , 27 ]. In a HCV core-
transgenic mouse model, expression of HCV core activates TGF-β signaling path-
way [ 35 ]. In cultured cells, HCV infection induces endoplasmic reticulum stress
and the unfolded protein response, which in turn triggers the generation of reactive
oxygen species (ROS) and activation of the p38 mitogen-activated protein kinase
(MAPK) signaling pathway, resulting in production of TGF-β [ 53 , 54 ]. Jee et al.
reported that there are higher expression levels of TGF-β in HCV-infected liver cells
from HCV patients, and HCV infection induces TGF-β production through HCV
E2-triggered overproduction of glucose-regulated protein 94 (GRP94) [ 55 ].
Conversely, overexpression of HCV NS5A protein inhibits TGF beta-mediated sig-
naling pathway in hepatoma cell lines [ 56 ].
8 HCV-Associated Cancers