The role of A20 as a master switch for the regulation of multiple distinct cell death pathways in hepatocarcinogenesis

TNFAIP3 is an NF-κB target gene whose encoded protein A20 terminates the activity of NF κB in response to TNF and microbial products such as lipopolysaccharides (LPS) in a negative feedback mechanism. Furthermore, it is also known as an inhibitor of TNF-induced apoptosis, while its molecular and functional role in the regulation of various programmed cell death (PCD) mechanisms and the development of hepatocellular carcinoma (HCC) has not yet been studied in depth, especially in relation to RIPK1 as a regulator of apoptosis and necroptosis.

Floxed A20 mice were crossed with mice expressing cre-recombinase under a liver paren-chymal cell specific (LPC) albumin promoter with alpha-fetoprotein enhancer. The resulting A20LPC-KO animals were further crossed with RIPK1LPC-KO mice. LPS injection was used as a model to simulate acute liver injury. Liver damage was assessed using serum transaminase level measurement and immunohistochemical stainings.

In the livers of A20LPC-KO mice, simultaneous apoptotic and necrotic damage could be ob-served after LPS injection. The additional deletion of RIPK1in the A20-deficient mice was related to an impressive spontaneous phenotype. This manifests itself in an altered hepatocyte architecture as early as 6 weeks of age, which develops into massive liver tumours by 50 weeks of age. Interestingly, HCC development in these mice was associated with NF-κB hyperactivation.

Our data suggest that A20 has a protective function in the liver due to inhibition of apoptosis and necroptosis. Furthermore, these findings implicate that A20 might be a crucial interaction partner of RIPK1 linking inflammation and PCD thus controlling HCC.

Publication History

Article published online:
23 January 2024