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8.2 HCV-Associated Hepatocellular Carcinoma (HCC)
Human viral oncogenesis shares common characteristics that oncoviruses are nec-
essary but not sufficient to trigger cancer development, and cancer develops after
many years of persistent infection with chronic inflammation or immune suppres-
sion [ 22 ]. HCV infection induces inflammation and immune-mediated liver dam-
age. During persistent viral infection, chronic inflammation results in prolonged
liver damage without virus clearance [ 23 ]. Immune-mediated liver damage prompts
repeated hepatocellular regeneration and progressive fibrosis, which in turn results
in a “cancer field” with genetically altered hepatocyte. Continued hepatocellular
turnover may select for cancer stem cells with growth advantages that eventually
develop hepatocellular carcinoma [ 24 ]. HCV infection or expression of HCV pro-
teins interferes with host cell proliferation and apoptosis. HCV infection triggers
oxidative stress, which may contribute to host genetic alteration and chronic inflam-
mation. Within the liver, HCV infection activates hepatic stellate cells (HSCs) to
produce excess extracellular matrix (ECM) and modulate fibrosis (Fig. 8.2). In
hepatocellular carcinoma progression, the epithelial-to-mesenchymal transition
Fig. 8.2 Model for HCV-induced carcinogenesis. HCV infection triggers oxidative stress and
production of reactive oxygen species (ROS); perturbs lipid metabolism, contributing to steatosis;
modulates cellular proliferation signaling pathway, and induces TGF-β production. Viral proteins
interfere with components for host DNA repair; viral components are recognized by innate sensors
to trigger inflammatory signaling cascades. ROS in turn contributes to host genetic alteration and
inflammation. Inflammation triggers adaptive immune response, resulting in immune-mediated
liver injury. Liver damage induces hepatocyte regeneration. TGF-β activates hepatic stellate cell to
become myoblast to secret excess extracellular matrix (ECM), which contributes to fibrosis and
influences cancer initiation and progression. The repeated hepatocyte regeneration may select for
cancer progenitors with aberrant proliferation to form a “cancer field” which finally develops into
hepatocellular carcinoma (HCC)
8 HCV-Associated Cancers