Loss of Cyclin E1 Attenuates Hepatitis and Hepatocarcinogenesis in a Mouse Model of Chronic Liver Injury

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2018 Mar 20

PMID 29551768

Citations 11

Authors

Haksier Ehedego

Antje Mohs

Bettina Jansen

Kanishka Hiththetiya

Piotr Sicinski

Christian Liedtke

Christian Trautwein

Affiliations

Soon will be listed here.

Abstract

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) leads to chronic hepatitis, liver fibrosis, and HCC as well as CcnE upregulation. To this end, we generated NEMO/CcnE1 and NEMO/CcnE2 double knockout mice and investigated age-dependent liver disease progression in these animals. Deletion of CcnE1 in NEMO 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 livers pointing to a unique, non-redundant function of CcnE1 in chronic hepatitis. Accordingly, basal compensatory hepatocyte proliferation in NEMO mice was reduced by concomitant ablation of CcnE1, but not after loss of CcnE2. In aged NEMO 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 mice.

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