RT Journal Article
T1 Cyclin E1 and cyclin-dependent kinase 2 are critical for initiation, but not for progression of hepatocellular carcinoma
A1 Sonntag, Roland
A1 Giebeler, Nives
A1 Nevzorova, Yulia
A1 Bangen, Jörg-Martín
A1 Fahrenkamp, Dirk
A1 Lambertz, Daniela
A1 Haas, Ute
A1 Hu, Wei
A1 Gassler, Nikolaus
A1 Cubero Palero, Francisco Javier
A1 Müller-Newen, Gerhard
A1 Abdallah, Ali T
A1 Weiskirchen, Ralf
A1 Ticconi, Fabio
A1 Costa, Ivan G
A1 Barbacid, Mariano
A1 Trautwein, Christian
A1 Liedtke, Christian
AB E-type cyclins E1 (CcnE1) and E2 (CcnE2) are regulatory subunits of cyclin-dependent kinase 2 (Cdk2) and thought to control the transition of quiescent cells into the cell cycle. Initial findings indicated that CcnE1 and CcnE2 have largely overlapping functions for cancer development in several tumor entities including hepatocellular carcinoma (HCC). In the present study, we dissected the differential contributions of CcnE1, CcnE2, and Cdk2 for initiation and progression of HCC in mice and patients. To this end, we tested the HCC susceptibility in mice with constitutive deficiency for CcnE1 or CcnE2 as well as in mice lacking Cdk2 in hepatocytes. Genetic inactivation of CcnE1 largely prevented development of liver cancer in mice in two established HCC models, while ablation of CcnE2 had no effect on hepatocarcinogenesis. Importantly, CcnE1-driven HCC initiation was dependent on Cdk2. However, isolated primary hepatoma cells typically acquired independence on CcnE1 and Cdk2 with increasing progression in vitro, which was associated with a gene signature involving secondary induction of CcnE2 and up-regulation of cell cycle and DNA repair pathways. Importantly, a similar expression profile was also found in HCC patients with elevated CcnE2 expression and poor survival. In general, overall survival in HCC patients was synergistically affected by expression of CcnE1 and CcnE2, but not through Cdk2. Our study suggests that HCC initiation specifically depends on CcnE1 and Cdk2, while HCC progression requires expression of any E-cyclin, but no Cdk2.
SN 1091-6490
YR 2018
FD 2018-09-11
LK https://hdl.handle.net/20.500.14352/98621
UL https://hdl.handle.net/20.500.14352/98621
LA eng
NO Sonntag R, Giebeler N, Nevzorova YA, Bangen JM, Fahrenkamp D, Lambertz D, Haas U, Hu W, Gassler N, Cubero FJ, Müller-Newen G, Abdallah AT, Weiskirchen R, Ticconi F, Costa IG, Barbacid M, Trautwein C, Liedtke C. Cyclin E1 and cyclin-dependent kinase 2 are critical for initiation, but not for progression of hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2018 Sep 11;115(37):9282-9287. doi: 10.1073/pnas.1807155115. Epub 2018 Aug 27. PMID: 30150405; PMCID: PMC6140539.
NO German Research Foundation
NO Ramón y Cajal Fellowship
NO Ministerio de Economía, Comercio y Empresa. Retos
NO Genomics Facility and by the Confocal Microscopy Facility of the Interdisciplinary Center for Clinical Research (IZKF)
NO Faculty of Medicine at RWTH Aachen University
DS Docta Complutense
RD 12 abr 2025