Genetic mouse studies suggest that the NF-κB pathway regulator NEMO (also known as IKKγ) 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(Δhepa) mice develop
chronic hepatitis characterized by increased hepatocyte apoptosis and proliferation that causes the development of
fibrosis and
hepatocellular carcinoma (HCC), 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(Δhepa)/p21(-/-) mice. Eight-week-old NEMO(Δhepa)/p21(-/-) animals displayed accelerated liver damage that was not associated with alterations in cell-cycle progression or the inflammatory response. However, livers from NEMO(Δhepa)/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(Δhepa)/p21(-/-) mice, demonstrating that DNA damage is induced via TNF. One-year-old NEMO(Δhepa)/p21(-/-) mice displayed greater numbers of HCC and severe
cholestasis compared with NEMO(Δhepa) animals. Therefore, p21 overexpression in NEMO(Δhepa) 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.