Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and represents the third leading cause of cancerrelated mortality [1]
We demonstrate here that p21 overexpression is protective in this model, as hepatocarcinogenesis and cholestasis are significantly enhanced upon deletion of p21 in NEMODhepa mice
We aimed to investigate the relevance of p21 for hepatocarcinogenesis in the NEMODhepa mouse model
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and represents the third leading cause of cancerrelated mortality [1]. HCC develops when the balance between cell proliferation and cell death is disrupted, and the subsequent aberrant proliferation leads to tumor growth. Cell proliferation is controlled by protein kinase complexes consisting of cyclins and cyclin-dependent kinases (Cdks), which regulate distinct phases of the cell cycle. Embryonic fibroblasts lacking p21 expression are significantly impaired in their ability to arrest in G1-phase in response to DNA damage [3], and in vivo experiments with p21 knockout mice. (p21À/À) revealed earlier hepatocyte DNA synthesis, cyclin/CDK kinase activation, and S-phase gene expression compared with wild-type mice in the partial hepatectomy (PH) model [4]. After PH mice with hepatic p21 overexpression displayed impaired hepatocyte proliferation [5]
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