1 p 21 ablation in liver enhances DNA damage , cholestasis and carcinogenesis

Genetic mouse studies suggest that the NFB pathway regulator NEMO (also known as IKK ) controls chronic inflammation and carcinogenesis in the liver. However the molecular mechanisms explaining the function of NEMO are not well defined. Here we report that overexpression of the cell cycle regulator p21 is a critical feature of liver inflammation and carcinogenesis caused by the loss of NEMO. NEMO mice develop chronic hepatitis characterized by increased hepatocyte apoptosis and proliferation that causes the development of fibrosis and hepatocellular carcinoma, similar to the situation in human liver disease. Having identified p21 overexpression in this model, we evaluated its role in disease progression and LPS-mediated liver injury in double mutant NEMO/p21 mice. Eight week-old NEMO/p21 animals displayed accelerated liver damage that was not associated with alterations in cell cycle progression or the inflammatory response. However, livers from NEMO/p21 mice displayed more severe DNA damage that was further characterized by LPS administration correlating with higher lethality of the animals. This phenotype was attenuated by genetic ablation of the TNF receptor TNF-R1 in NEMO/p21 mice, demonstrating that DNA damage is induced via TNF. One year old NEMO/p21 mice displayed greater numbers of hepatocellular carcinoma and severe cholestasis compared to NEMO animals. Therefore, p21 overexpression in NEMO animals protects against DNA damage, acceleration of hepatocarcinogenesis and cholestasis. Taken together, our findings illustrate how loss of NEMO promotes chronic liver inflammation and carcinogenesis, and they identify a novel protective role for p21 against the generation of DNA damage. on April 13, 2017. © 2015 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on January 21, 2015; DOI: 10.1158/0008-5472.CAN-14-1356