Constitutive Activation of the Tumor Suppressor p53 in Hepatocytes Paradoxically Promotes Non–Cell Autonomous Liver Carcinogenesis

Abstract

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.

ZNF385A and ZNF346 Serve as Prognostic Biomarkers Associated with an Inflamed Immunosuppressive Tumor Microenvironment in Hepatocellular Carcinoma

“…The functional enrichment analysis of co-expressed genes and GSEA analysis indicated that ZNF385A and ZNF346 were significantly related to cancer-related processes such as cell cycle, G2M checkpoint, DNA replication, and adherens junctions, and they were significantly enriched in cancer-related pathways such as p53, VEGF, and Wnt signaling pathways ( Figure 4 F,G). A recent study demonstrated that activated p53 expression was positively correlated with the level of apoptosis and subsequent cancer development in chronic liver diseases [ 22 ]. The VEGF and Wnt signaling pathways have been widely reported to contribute to the carcinogenic process of HCC [ 23 , 24 ].…”

Targeting p53 pathways: mechanisms, structures and advances in therapy

“… 117 Another group knocked out MDM2 in hepatocyte-specific KRAS G12D mutant mice and observed p53 accumulation in mouse hepatocytes. 196 These p53-activated mice exhibited increased inflammatory responses, hepatocyte apoptosis, and senescence-associated secretory phenotype, leading to the facilitation of a carcinogenic microenvironment 196 , 197 (Fig. 3 ).…”

“…The development of hepatocellular carcinoma and other related phenotypes no longer occurred after knockdown of TP53 , suggesting that p53-accumulated mice do promote the development of hepatocellular carcinoma. 196 Cellular activities regulated by p53 are integrated into tumor suppressive functions, but p53-induced regulation of certain elements may also provide a survival advantage for tumors (Fig. 3 ).…”

Hedgehog Signaling: Implications in Liver Pathophysiology

“…For example, mice with global deletion of superoxide dismutase exhibit accelerated aging, steatotic liver disease, liver fibrosis, hepatocellular carcinoma, and a shortened lifespan 72 . Constitutive activation of p53 in murine hepatocytes induces their senescence but expands highly proliferative hepatic progenitor populations that develop chromosomal instability and eventually undergo malignant transformation 73 . Diet-induced and genetic obesity evoke changes in the gut microbiome that increase liver exposure to toxic bile acids that induce senescence in hepatic stellate cells and exacerbate susceptibility to liver cancer 74 .…”