Abstract A32: Studying circadian disruption as a novel risk factor of hepatocellular carcinoma using mouse models

Hepatocellular carcinoma (HCC) is previously considered a rare type of cancer in the Western world, but shows an annual increase of 3.5% since 1992 and is currently ranked second only to pancreatic cancer for cancer-related deaths in the United States due to its lack of early detection markers and poor prognosis. HCC is particularly difficult to treat because its development impairs liver normal drug metabolic function leading to chemoresistant. Although chronic infections with hepatitis B or C virus are the major risk factors for HCC worldwide, liver metabolic diseases associated with obesity such as non-alcoholic fatty liver diseases, diabetes mellitus and iron-storage diseases, account for the majority of HCC cases in the U.S. The rapid increase in obesity and obesity-associated metabolic disease in recent years suggests that the incidence of metabolic dysfunction-induced HCC is likely continually to increase in the States in the future. However, most existing HCC animal models develop tumors either following the treatment of carcinogens or ablation of a key liver tumor suppression pathway, which do not follow the same pathophysiological mechanisms of tumor initiation and progression as metabolic disorder-induced HCC in humans. Hence, there is a critical need to establish animal models that develop spontaneous HCC in response to chronic metabolic stress to study the mechanism of metabolic dysfunction-induced HCC, identify early detection markers associated with these types of HCC, and investigate the role of liver metabolic disruption in anticancer treatment. Most physiological processes including nutrient intake, storage and metabolism follows a circadian rhythm in mammals since our homeostatic systems are shaped by the evolutionary adaptation to daily light/dark changes in the environment. Disruption of circadian homeostasis leads to a coupled increase in the risk of obesity, liver metabolic syndromes and cancers in both night-shift human workers and animal models. We have previously reported that circadian gene-mutant mouse models show a significant increased risk to cancer. Our recent studies have revealed that disrupting circadian rhythm in wild-type mice by chronic jet-lag following a schedule that mimics the night-shift working schedules in humans leads to a progressive deregulation of multiple plasma and hepatic metabolic parameters in the serum and induction of multiple liver metabolic syndromes including hepatosteatosis as well as liver inflammation and uncontrolled hepatocytes and bile duct proliferation prior to HCC onset. Genome-wide array analyses have led to identify a time-dependent deregulation of all known key pathways controlling metabolism, energy storage, redox levels, cell proliferation, inflammatory response and tumor suppression in the liver of mice lacking circadian homeostasis. Our studies have established an excellent mouse model to study the role of metabolic dysfunction in spontaneous HCC induction. Further studies will lead to elucidate the mechanism of HCC induction by chronic metabolic disruption and identify novel serum and hepatic biomarkers for HCC early detection and treatment. Citation Format: Nicole M. Kettner, David D. Moore, Loning Fu. Studying circadian disruption as a novel risk factor of hepatocellular carcinoma using mouse models. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A32.