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 (NEMOΔhepa) leads to chronic hepatitis, liver fibrosis, and HCC as well as CcnE upregulation. To this end, we generated NEMOΔhepa/CcnE1−/− and NEMOΔhepa/CcnE2−/− double knockout mice and investigated age-dependent liver disease progression in these animals. Deletion of CcnE1 in NEMOΔhepa mice decreased basal liver damage and reduced spontaneous liver inflammation in young mice. In contrast, loss of CcnE2 did not affect liver injury in NEMOΔhepa livers pointing to a unique, non-redundant function of CcnE1 in chronic hepatitis. Accordingly, basal compensatory hepatocyte proliferation in NEMOΔhepa mice was reduced by concomitant ablation of CcnE1, but not after loss of CcnE2. In aged NEMOΔhepa 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 NEMOΔhepa mice.
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Aigelsreiter A, Haybaeck J, Schauer S, Kiesslich T, Bettermann K, Griessbacher A, et al. NEMO expression in human hepatocellular carcinoma and its association with clinical outcome. Hum Pathol. 2012;43:1012–9.
Bisteau X, Caldez MJ, Kaldis P. The complex relationship between liver cancer and the cell cycle: a story of multiple regulations. Cancers. 2014;6:79–111.
Jung YJ, Lee KH, Choi DW, Han CJ, Jeong SH, Kim KC, et al. Reciprocal expressions of cyclin E and cyclin D1 in hepatocellular carcinoma. Cancer Lett. 2001;168:57–63.
Li K, Lin SY, Brunicardi FC, Seu P. Use of RNA interference to target cyclin E-overexpressing hepatocellular carcinoma. Cancer Res. 2003;63:3593–7.
Clurman BE, Sheaff RJ, Thress K, Groudine M, Roberts JM. Turnover of cyclin E by the ubiquitin-proteasome pathway is regulated by cdk2 binding and cyclin phosphorylation. Genes Dev. 1996;10:1979–90.
Geng Y, Yu Q, Sicinska E, Das M, Schneider JE, Bhattacharya S, et al. Cyclin E ablation in the mouse. Cell . 2003;114:431–43.
Parisi T, Beck AR, Rougier N, McNeil T, Lucian L, Werb Z, et al. Cyclins E1 and E2 are required for endoreplication in placental trophoblast giant cells. EMBO J. 2003;22:4794–803.
Ortega S, Prieto I, Odajima J, Martin A, Dubus P, Sotillo R, et al. Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat Genet. 2003;35:25–31.
Geng Y, Lee YM, Welcker M, Swanger J, Zagozdzon A, Winer JD, et al. Kinase-independent function of cyclin E. Mol Cell. 2007;25:127–39.
Minella AC, Loeb KR, Knecht A, Welcker M, Varnum-Finney BJ, Bernstein ID, et al. Cyclin E phosphorylation regulates cell proliferation in hematopoietic and epithelial lineages in vivo. Genes Dev. 2008;22:1677–89.
Nevzorova YA, Tschaharganeh D, Gassler N, Geng Y, Weiskirchen R, Sicinski P, et al. Aberrant cell cycle progression and endoreplication in regenerating livers of mice that lack a single E-type cyclin. Gastroenterology. 2009;137:691–703. e1-6
Nevzorova YA, Bangen JM, Hu W, Haas U, Weiskirchen R, Gassler N, et al. Cyclin E1 controls proliferation of hepatic stellate cells and is essential for liver fibrogenesis in mice. Hepatology. 2012;56:1140–9.
Pok S, Wen V, Shackel N, Alsop A, Pyakurel P, Fahrer A, et al. Cyclin E facilitates dysplastic hepatocytes to bypass G1/S checkpoint in hepatocarcinogenesis. J Gastroenterol Hepatol. 2013;28:1545–54.
Luedde T, Beraza N, Kotsikoris V, van Loo G, Nenci A, De Vos R, et al. Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell. 2007;11:119–32.
Beraza N, Malato Y, Sander LE, Al-Masaoudi M, Freimuth J, Riethmacher D, et al. Hepatocyte-specific NEMO deletion promotes NK/NKT cell- and TRAIL-dependent liver damage. J Exp Med. 2009;206:1727–37.
Ehedego H, Boekschoten MV, Hu W, Doler C, Haybaeck J, Gabetaler N, et al. p21 ablation in liver enhances DNA damage, cholestasis, and carcinogenesis. Cancer Res. 2015;75:1144–55.
Chuma M, Sakamoto M, Yamazaki K, Ohta T, Ohki M, Asaka M, et al. Expression profiling in multistage hepatocarcinogenesis: identification of HSP70 as a molecular marker of early hepatocellular carcinoma. Hepatology. 2003;37:198–207.
Geng Y, Yu Q, Whoriskey W, Dick F, Tsai KY, Ford HL, et al. Expression of cyclins E1 and E2 during mouse development and in neoplasia. Proc Natl Acad Sci USA. 2001;98:13138–43.
Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.
Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature. 2004;431:461–6.
Bangen JM, Hammerich L, Sonntag R, Baues M, Haas U, Lambertz D, et al. Targeting CCl4 -induced liver fibrosis by RNA interference-mediated inhibition of cyclin E1 in mice. Hepatology. 2017;66:1242–57.
Hu W, Nevzorova YA, Haas U, Moro N, Sicinski P, Geng Y, et al. Concurrent deletion of cyclin E1 and cyclin-dependent kinase 2 in hepatocytes inhibits DNA replication and liver regeneration in mice. Hepatology. 2014;59:651–60.
Malato Y, Ehedego H, Al-Masaoudi M, Cubero FJ, Bornemann J, Gassler N, et al. NF-kappaB essential modifier is required for hepatocyte proliferation and the oval cell reaction after partial hepatectomy in mice. Gastroenterology. 2012;143:1597–608 e11.
This work was supported by a grant of the German Cancer Foundation (Deutsche Krebshilfe) Grant Nr. 107682, the SFB TRR/57 and the Interdisciplinary Centre for Clinical Research (IZKF Aachen) within the Faculty of Medicine; RWTH Aachen.
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The authors declare that they have no conflict of interest.
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Ehedego, H., Mohs, A., Jansen, B. et al. Loss of Cyclin E1 attenuates hepatitis and hepatocarcinogenesis in a mouse model of chronic liver injury. Oncogene 37, 3329–3339 (2018). https://doi.org/10.1038/s41388-018-0181-8
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