Loss of Cyclin E1 attenuates hepatitis and hepatocarcinogenesis in a mouse model of chronic liver injury.

Chronic liver injury triggers liver fibrosis and hepatocellular carcinoma (HCC), the third leading cause of cancer-related mortality. Cyclin E1 (CcnE1, formerly designated Cyclin E) is a regulatory subunit of the Cyclin-dependent kinase 2 (CDK2). It is overexpressed in approximately 70% of human HCCs correlating with poor prognosis, while the relevance of its orthologue Cyclin E2 (CcnE2) is unclear. Hepatocyte-specific deletion of NF-kappa-B essential modulator (NEMO^Δhepa) leads to chronic hepatitis, liver fibrosis, and HCC as well as CcnE upregulation. To this end, we generated NEMO^Δhepa/CcnE1^-/- and NEMO^Δhepa/CcnE2^-/- double knockout mice and investigated age-dependent liver disease progression in these animals. Deletion of CcnE1 in NEMO^Δhepa mice decreased basal liver damage and reduced spontaneous liver inflammation in young mice. In contrast, loss of CcnE2 did not affect liver injury in NEMO^Δhepa livers pointing to a unique, non-redundant function of CcnE1 in chronic hepatitis. Accordingly, basal compensatory hepatocyte proliferation in NEMO^Δhepa mice was reduced by concomitant ablation of CcnE1, but not after loss of CcnE2. In aged NEMO^Δhepa mice, loss of CcnE1 resulted in significant reduction of liver tumorigenesis, while deletion of CcnE2 had no effect on HCC formation. CcnE1, but not its orthologue CcnE2, substantially contributes to hepatic inflammatory response, liver disease progression, and hepatocarcinogenesis in NEMO^Δhepa mice.

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