Investigation of the effects of hepatitis C virus (HCV) infection on cellular responses to chemical carcinogen exposures
PI: Stanley Lemon, MD; Co-I: David McGivern, Ph.D.; Co-I: Istvan Boldogh, Ph.D.
Liver cancer frequently develops in a setting of combined chemical and infectious carcinogen exposures. Chronic infection with the hepatitis C virus (HCV) is associated with an increased risk for liver cancer. Chronic HCV infection is associated with elevated levels of reactive oxygen species (ROS) mediated by the HCV core protein, and immune-mediated inflammation, both of which are thought to contribute to HCV-associated carcinogenesis. Cancer typically develops 2-3 decades after infection in the background of cirrhosis. Progression to liver cancer is variable among chronically-infected patients suggesting the involvement of host and environmental factors. For another virus that is associated with liver cancer, hepatitis B virus, there is evidence that liver-specific expression of virus-encoded proteins increases the susceptibility of mice to tumor development following exposure to the hepatocarcinogen diethylnitrosamine (DEN). Furthermore, in vitro studies have demonstrated that HCV-encoded proteins can interact with and modulate several host tumor suppressor proteins involved in DNA damage responses including p53, Rb and ATM. The proposed study aims to test the hypothesis that HCV infection reduces the ability of hepatocytes to respond to genotoxic insults and DNA damage caused by environmental exposures and oxidative stress.
