Pathogenesis and prevention of hepatitis C virus-induced hepatocellular carcinoma

Yujin Hoshida, Bryan C. Fuchs, Nabeel Bardeesy, Thomas F. Baumert, Raymond T. Chung
2014 Journal of Hepatology  
Hepatitis C virus (HCV) is one of the major aetiologic agents that causes hepatocellular carcinoma (HCC) by generating an inflammatory, fibrogenic, and carcinogenic tissue microenvironment in the liver. HCV-induced HCC is a rational target for cancer preventive intervention because of the clear-cut high-risk condition, cirrhosis, associated with high cancer incidence (1% to 7% per year). Studies have elucidated direct and indirect carcinogenic effects of HCV, which have in turn led to the
more » ... fication of candidate HCC chemoprevention targets. Selective molecular targeted agents may enable personalized strategies for HCC chemoprevention. In addition, multiple experimental and epidemiological studies suggest the potential value of generic drugs or dietary supplements targeting inflammation, oxidant stress, or metabolic derangements as possible HCC chemopreventive agents. While the successful use of highly effective direct-acting antiviral agents will make important inroads into reducing long-term HCC risk, there will remain an important role for HCC chemoprevention even after viral cure, given the persistence of HCC risk in persons with advanced HCV fibrosis, as shown in recent studies. The successful development of cancer preventive therapies will be more challenging compared to cancer therapeutics because of the requirement for larger and longer clinical trials and the need for a safer toxicity profile given its use as a preventive agent. Molecular biomarkers to selectively identify high-risk population could help mitigate these challenges. Genome-wide, unbiased molecular characterization, high-throughput drug/gene screening, experimental model-based functional analysis, and systems-level in silico modelling are expected to complement each other to facilitate discovery of new HCC chemoprevention targets and therapies. Ó Open access under CC BY-NC-ND license. Cellular proliferation and survival pathways Artificial over-expression of HCV proteins, e.g., core, NS3, and NS5A promotes cellular proliferation, transformation, anchorage-independent growth, and/or tumour formation in mice, suggesting their direct contribution in activating oncogenic molecular pathways [20] [21] [22] [23] . The core protein inhibits tumour suppressor genes TP53, TP73, and RB1 as well as negative Clinical Course
doi:10.1016/j.jhep.2014.07.010 pmid:25443348 pmcid:PMC4435677 fatcat:36jjq5zegjb3xblu7ko3yrt534