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139

are any driver mutations for HCC development remains to be elucidated in the

future studies [ 24 ]. The lack of reliable animal model recapitulating the HCV infec-

tion and HCC development hampers the studies to address these questions in vivo.

The only natural animal model of HCV, chimpanzee, mainly resolves HCV infec-

tion. A chimpanzee infected with a cell culture-derived genotype 1a virus with

culture- adaptive mutations develops persistent infection with chronic hepatitis,

which may provide an opportunity to address the molecular mechanism of HCC

[ 111 ]. However due to the limitation of accessibility of chimpanzee model, small

animal models for HCV infection are needed. HCV transgenic mice expressing

HCV core develop HCC without obvious inflammation [ 64 ]. Recently an immune-

competent mouse model with transgenic human CD81 and occludin genes supports

HCV the entire life cycle and develops fibrotic and cirrhotic progression [ 112 ].

These animal models may provide tools to dissect the molecular mechanisms of

HCC development and identify the key molecular signaling pathways contributing

to HCC development.

HCV-associated HCC often develops after many years. It is beneficial to identify

the molecular alterations during early time of HCC development for diagnosis and

prognosis. Using the high-throughput technologies may help identify the host

genetic alterations associated with HCC development [ 113 ] (Table 8.1).

Acknowledgments Supported in part by grants from National Basic Research Program of China
2015CB554301 and Sino-German Transregional Collaborative Research and National Natural
Science Foundation of China for international collaboration 81461130019.

References

1. Lavanchy D (2009) The global burden of hepatitis C. Liver Int 29(Suppl 1):74–81


2. Forner A, Llovet JM, Bruix J (2012) Hepatocellular carcinoma. Lancet 379:1245–1255


3. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M (1989) Isolation of
   a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science
   244:359–362

Table 8.1 HCV proteins interfere with cellular proliferation signaling pathways

HCV protein Experiment system Signaling pathway Reference

Polyprotein Transgenic mouse model c-myc [ 34 ]

Core, E2, NS5A Transgenic mouse model, HCV

replicon, overexpression in cell line

TGF-β [ 35 , 55 , 56 ]

Core Transgenic mouse model Oxidative stress [ 65 ]

Core, NS5A Overexpression in cell line wnt/beta-catenin [ 28 , 29 ]

NS5A,

polyprotein

Overexpression in cell line; HCV

subgenomic replicon

PI3K [ 30 , 31 ]

NS5B Overexpression in cell line Rb, CINP [ 32 , 38 ]

NS3/4A Overexpression in cell line AT M [ 48 ]

8 HCV-Associated Cancers