Molecular pathology : the roles of P53 in the oxidative stress and DNA damage responses in chronic liver disease and hepatocellular carcinoma

Abstract

Non-alcoholic fatty liver disease (NAFLD) has become the commonest form of chronic liver disease in western nations and is rapidly rising in the Asia-Pacific. As yet treatments are limited to diet modification and life style change, which is rarely effective. NAFLD is associated with an increasing risk of developing hepatocellular carcinoma (HCC), which is also increasing markedly and is a significant cause of death. The disease progression is difficult to study in humans as invasive procedures are needed. We have developed a mouse model reflecting the human condition to investigate mechanisms of this disease and potential therapeutic interventions. We used C3H/He mice, which develop obesity and impaired glucose tolerance with age, and explored the effect of an American lifestyle diet. The mice developed features of the metabolic syndrome and NAFLD, including non-alcoholic steatohepatitis (NASH), which was associated with an increase in DNA damage and the development of HCC. Interesting findings were observed with an anti-oxidant (bucillamine) and an FXR agonist (PX20606), but neither prevented HCC development. As a key responder to DNA damage, TP53 was explored in the model. In general, TP53 mutation is reported in around 33% of HCC cases and is usually linked with aflatoxin exposure and viral hepatitis infection, but in the Western world the incidence of TP53 mutation is lower. In our NAFLD model, all the tumours which developed were of wild-type TP53 status. This encouraged us to explore exploiting this pathway by testing the ability of small molecule inhibitors of the MDM2-p53 binding interaction to activate p53 in a non-genotoxic manner as a potential treatment for TP53 wild-type HCC. Promising results were obtained, with highly significant growth inhibitory effects in vitro and in vivo (NSG xenograft model) in TP53 wild-type liver cancer cell lines through the induction of senescence. Combination studies in vitro also showed that the effect of MDM2-p53 binding antagonists could be potentiated by inhibition of the WIP1/PPM1D phosphatase. Our study shows that targeting the p53 pathway is worthy of further exploration for patients with liver cancer.