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Cyclin E1 and Cyclin-Dependent Kinase 2 Are Critical for Initiation, but Not for Progression of Hepatocellular Carcinoma

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Cyclin E1 and Cyclin-Dependent Kinase 2 Are Critical for Initiation, but Not for Progression of Hepatocellular Carcinoma Cyclin E1 and cyclin-dependent kinase 2 are critical for initiation, but not for progression of hepatocellular carcinoma Roland Sonntaga,1, Nives Giebelera,1, Yulia A. Nevzorovaa, Jörg-Martin Bangena, Dirk Fahrenkampb, Daniela Lambertza, Ute Haasa, Wei Hua, Nikolaus Gasslerc,2, Francisco Javier Cuberoa,3, Gerhard Müller-Newenb, Ali T. Abdallahd, Ralf Weiskirchene, Fabio Ticconif, Ivan G. Costaf, Mariano Barbacidg,4, Christian Trautweina, and Christian Liedtkea,4 aDepartment of Internal Medicine III, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH), 52074 Aachen, Germany; bInstitute of Biochemistry and Molecular Biology, University Hospital RWTH, 52074 Aachen, Germany; cInstitute of Pathology, University Hospital RWTH, 52074 Aachen, Germany; dInterdisciplinary Center for Clinical Research, University Hospital RWTH, 52074 Aachen, Germany; eInstitute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, University Hospital RWTH, 52074 Aachen, Germany; fInstitute for Computational Genomics, RWTH Aachen University, 52074 Aachen, Germany; and gMolecular Oncology, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain Contributed by Mariano Barbacid, August 3, 2018 (sent for review April 27, 2018; reviewed by Steven Dooley, Satdarshan Pal Singh Monga, and Luca Valenti) E-type cyclins E1 (CcnE1) and E2 (CcnE2) are regulatory subunits of liver regeneration following partial hepatectomy (PH), whereas cyclin-dependent kinase 2 (Cdk2) and thought to control the compound deletion of CcnE1 and CcnE2 substantially inhibited transition of quiescent cells into the cell cycle. Initial findings hepatocyte proliferation and liver mass restoration (3, 4). indicated that CcnE1 and CcnE2 have largely overlapping functions Hepatocellular carcinoma (HCC) is one of the most frequent for cancer development in several tumor entities including hepa- tumor diseases worldwide with growing incidence and poor tocellular carcinoma (HCC). In the present study, we dissected the prognosis. In most cases, HCC develops on the basis of chronic differential contributions of CcnE1, CcnE2, and Cdk2 for initiation hepatitis in a multistep process involving frequent up-regulation and progression of HCC in mice and patients. To this end, we or amplification of E-type cyclins and many other cell cycle- tested the HCC susceptibility in mice with constitutive deficiency related proteins as reviewed elsewhere (5). However, the detailed for CcnE1 or CcnE2 as well as in mice lacking Cdk2 in hepatocytes. contribution of the individual E-cyclins for HCC development has Genetic inactivation of CcnE1 largely prevented development of barely been investigated. We recently observed that inhibition of liver cancer in mice in two established HCC models, while ablation CcnE1 may attenuate HCC development in a genetic model of of CcnE2 had no effect on hepatocarcinogenesis. Importantly, CcnE1-driven HCC initiation was dependent on Cdk2. However, isolated primary hepatoma cells typically acquired independence Significance on CcnE1 and Cdk2 with increasing progression in vitro, which was associated with a gene signature involving secondary induction of The two E-type cyclins E1 and E2 are known to interact with CcnE2 and up-regulation of cell cycle and DNA repair pathways. Cdk2 and are thought to trigger cell cycle activity in carcino- Importantly, a similar expression profile was also found in HCC genesis. However, the individual contributions of cyclin E1, patients with elevated CcnE2 expression and poor survival. In cyclin E2, and Cdk2 for initiation and progression of hepato- general, overall survival in HCC patients was synergistically cellular carcinoma (HCC) are unknown. In the present study, we affected by expression of CcnE1 and CcnE2, but not through discovered that only cyclin E1—but not cyclin E2—is essential Cdk2. Our study suggests that HCC initiation specifically depends for initiation of liver cancer and requires Cdk2. Unexpectedly, on CcnE1 and Cdk2, while HCC progression requires expression of advanced liver cancer progression can be mediated in presence any E-cyclin, but no Cdk2. of any E-cyclin, but in a Cdk2-independent manner. We iden- tified the specific expression profiles of cyclin E1-dependent HCC | liver | cell cycle | diethylnitrosamine | DNA repair and cyclin E1-independent hepatoma cells. These signatures are useful for predicting patient prognosis and for developing he mammalian cell cycle is controlled by cyclin-dependent novel cyclin E-based HCC therapies. Tkinases (Cdk) and cyclins acting as Cdk-regulatory subunits. Author contributions: R.S., N. Giebeler, C.T., and C.L. designed research; R.S., N. Giebeler, Specific cyclin/Cdk complexes regulate transition through the Y.A.N., J.-M.B., D.L., U.H., W.H., and F.J.C. performed research; R.W. and M.B. contributed distinct phases of the cell cycle by phosphorylation of phase- new reagents/analytic tools; D.F., N. Gassler, G.M.-N., A.T.A., F.T., and I.G.C. analyzed data; specific substrates (1). Extracellular mitogenic signals induce and R.S. and C.L. wrote the paper. expression of D-type cyclins, which drive progression through G1 Reviewers: S.D., Heidelberg University; S.P.S.M., University of Pittsburgh; and L.V., Univer- phase via binding and activation of Cdk4 and Cdk6. These ki- sity of Milano. nases phosphorylate and inactivate the retinoblastoma protein The authors declare no conflict of interest. (Rb). Rb phosphorylation is completed by Cdk2 kinase in com- Published under the PNAS license. plex with E-type cyclins (CcnE1, CcnE2) shortly before S-phase Data deposition: The data reported in this paper have been deposited in the Gene Ex- entry, leading to the activation of E2F transcription factors pression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE111079). and cell cycle-related genes. Despite their proposed important 1 function for S-phase entry, genetic knockout studies in mice R.S. and N. Giebeler contributed equally to this work. 2 revealed that CcnE1, CcnE2, or Cdk2 are not essential for Present address: Institute of Pathology, Klinikum Braunschweig, 38118 Braunschweig, Germany. 3 proliferation of normal tissue cells during development, ho- Present addresses: Department of Immunology, Complutense University School of Med- icine, 28040 Madrid, Spain; and Hospital 12 de Octubre Health Research Institute meostasis, and regeneration. Even compound inactivation of (imas12), 28040 Madrid, Spain. CcnE1 and CcnE2 in continuous growing murine embryonic fi- 4To whom correspondence may be addressed. Email: [email protected] or cliedtke@ broblasts allowed proper S-phase transition and proliferation but ukaachen.de. prevented at least cell cycle reentry after serum starvation and This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. malignant transformation in vitro (2). We recently demonstrated 1073/pnas.1807155115/-/DCSupplemental. that deletion of a single E-cyclin had only a modest effect on Published online August 27, 2018. 9282–9287 | PNAS | September 11, 2018 | vol. 115 | no. 37 www.pnas.org/cgi/doi/10.1073/pnas.1807155115 Downloaded by guest on September 25, 2021 − − chronic hepatitis (6). Here, we aimed to genetically dissect the CcnE1 / mice displayed substantially reduced average tumor − − precise contribution of CcnE1, CcnE2, or Cdk2 for HCC initiation numbers and tumor size in comparison with WT or CcnE2 / mice and/or progression. We show that CcnE1 has a Cdk2-dependent, (Fig. 1E). Histologically, liver sections from DEN-treated WT and − − unique, and critical function for initiation of liver cancer, while CcnE2 / animals revealed strong dysplasia, abnormal tissue ar- − − HCC progression is controlled by alternative mechanisms in- chitecture, and excessive cell proliferation, whereas CcnE1 / liver dependent of Cdk2 activity. sections appeared mostly normal with infrequent small pre- cancerous lesions and infrequent occurrence of proliferating he- Results patocytes (SI Appendix, Fig. S2B). In DEN-treated WT mice, CcnE1—but Not CcnE2—Is Critical for DEN-Driven Hepatic Tumor CcnE1 was almost exclusively induced in hepatocytes within dys- Development. To assess the role of E-cyclins for hepatocarcino- plastic areas, but barely detectable (<0.1%) in nonparenchymal − − − − + + genesis, 2-wk-old WT, CcnE1 / , and CcnE2 / mice were cells such as CD45 leukocytes or α-SMA myofibroblasts (SI − − treated with a single dose of the hepatocarcinogen diethylni- Appendix,Fig.S3A). HCC formation in WT and CcnE2 / mice trosamine (DEN) and euthanized 22 wk or 38 wk later (SI Ap- was associated with up-regulation of CcnE1, but WT HCC did not pendix, Fig. S1A). Similar expression levels of Cytochrome P450 show elevated CcnE2 expression (SI Appendix,Fig.S3B). On the − − 2E1 (Cyp2E1) in all groups before and after treatment excluded cellular level, the few HCC nodules found in CcnE1 / livers were an effect of E-cyclin ablation on DEN metabolism and its bio- characterized by small clusters of CcnE2-expressing cells at the activation (SI Appendix, Fig. S1B). Twenty-two weeks after DEN edge of dysplastic lesions (SI Appendix, Fig. S3C). CcnE2 protein treatment, alanine transaminase (ALT) activities—an indicator was predominantly localized in the cytoplasm and only occasion- of overall liver injury—and relative liver weights in all mice were ally detected in the nucleus. Importantly, we did not detect CcnE2 at normal levels (SI Appendix, Fig. S1 C and D). However, small protein in livers
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