Abstract 1728: Overactivation of tumor suppressor P53 in hepatocytes promotes hepatocarcinogenesis

Abstract Aim: p53 is a tumor suppressor and its dysfunction promotes carcinogenesis of several organs including the liver. Meanwhile, p53 is reported to be overactivated in non-tumorous liver tissues of patients with chronic liver diseases, presumably due to several stressful stimuli to hepatocytes, including viral infection, ethanol exposure, fat accumulation. The aim of this study is to clarify the impact of p53 overactivation on hepatocarcinogenesis. Methods: To induce hepatocyte-specific overactivation of p53 in liver cancer models, hepatic Mdm2, a negative regulator of p53, was genetically ablated in diethylnitrosoamine (DEN)-treated mice (Alb-CreMdm2fl/fl) and liver-specific constitutive-active Kras-mutant knock-in mice (Alb-CreKrasLSL-G12DMdm2fl/fl called as KrasG12DΔMdm2 mice). To analyze the significance of p53, hepatic p53 was deleted in Mdm2-wild KrasG12D mice (Alb-CreKrasLSL-G12DMdm2+/+p53fl/fl) and KrasG12DΔMdm2 mice (Alb-CreKrasLSL-G12DMdm2fl/flp53fl/fl). Results: Mdm2 deletion significantly elevated serum ALT levels and increased tumor penetrance in both DEN-treated mice and Kras-mutant mice, suggesting that p53 overactivation accelerated hepatocarcinogenesis. KrasG12DΔMdm2 mice upregulated hepatic expressions of pro-apoptotic molecules (p16, p21, Bax, Noxa), number of TUNEL positive hepatocytes and serum caspase-3/7 levels, indicating accelerated hepatocyte apoptosis. They also increased the number of β-galactosidase positive hepatocytes and upregulated hepatic inflammatory cytokines (Tnf, Ccl2, Il-1β), suggesting senescence-associated secretory phenotype (SASP). Expressions of hepatic progenitor cell (HPC) markers (Afp, Epcam, Ck7, Ck19, Cd90, Cd133, Dlk1) were up-regulated in their liver. HPC marker staining suggested that liver tumors in KrasG12DΔMdm2 mice may originate from HPCs. All the phenotypes including accelerated hepatocyte apoptosis, SASP and emergence of HPCs in KrasG12DΔMdm2 mice were significantly alleviated by p53 deletion. Most importantly, deletion of p53 significantly decelerated hepatocarcinogenesis in those mice, indicating that p53 overactivation was responsible for the accelerated hepatocarcinogenesis. In sharp contrast, p53 deletion significantly accelerated hepatocarcinogenesis in Mdm2-wild Kras-mutant mice, confirming the tumor suppressive role of normal level of p53 in the liver. Conclusion: Whereas p53 deletion accelerated hepatocarcinogenesis, p53 overactivation induced liver injury and activation of HPCs, leading to the acceleration of hepatocarcinogenesis. p53 overactivation in hepatocytes might be associated with liver cancer development in patients with chronic liver diseases. Citation Format: Yuki Makino. Overactivation of tumor suppressor P53 in hepatocytes promotes hepatocarcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1728.