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In chronic liver diseases (CLDs), p53 is constitutively activated in hepatocytes due to various etiologies as viral infection, ethanol exposure, or lipid accumulation. This study was aimed to clarify the significance of p53 activation on the pathophysiology of CLDs. In Kras-mutant liver cancer model, Mdm2, a negative regulator of p53, was specifically deleted in hepatocytes (Alb-Cre KrasLSL-G12D Mdm2fl/fl) (LiKM; KrasG12D mutation and Mdm2 loss in the liver). Accumulation of p53 and up-regulation of its downstream genes were observed in hepatocytes in LiKM mice. LiKM mice showed liver inflammation accompanied by hepatocyte apoptosis, senescence-associated secretory phenotype (SASP), and the emergence of hepatic progenitor cells (HPCs). More importantly, Mdm2 deletion promoted non-cell autonomous development of liver tumors. Organoids generated from HPCs harbored tumor-formation ability, when subcutaneously inoculated into NOD/Shi-scid/IL-2Rγ (null) mice. Treatment with acyclic retinoid suppressed growth of HPCs in vitro and inhibited tumorigenesis in LiKM mice. All of the phenotypes in LiKM mice, including accelerated liver tumorigenesis, were negated by further deletion of p53 in hepatocytes (Alb-Cre KrasLSL-G12D Mdm2fl/fl p53fl/fl). Activation of hepatic p53 was noted in liver biopsy samples obtained from 182 CLD patients, in comparison to 23 normal liver samples without background liver diseases. In CLD patients, activity of hepatic p53 were positively correlated with the expression of apoptosis, SASP, HPC-associated genes and tumor incidence in the liver after biopsy. In conclusion, activation of hepatocyte p53 creates a microenvironment prone to tumor formation from HPCs. Optimization of p53 activity in hepatocytes is important to prevent CLD patients from hepatocarcinogenesis.

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