Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 37, Pages 9282-9287Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1807155115
Keywords
HCC; liver; cell cycle; diethylnitrosamine; DNA repair
Categories
Funding
- German Research Foundation (DFG) [LI1045/2-4, SFB/TRR57, P13, NE 2128/2-1]
- Ramon y Cajal Fellowship [RYC2015-17438, RYC-2014-15242]
- MINECO Retos [SAF2016-78711]
- Genomics Facility of the Interdisciplinary Center for Clinical Research (IZKF) Aachen
- Confocal Microscopy Facility of the Interdisciplinary Center for Clinical Research (IZKF) Aachen
- IZKF Faculty of Medicine at RWTH Aachen University [IZKF/O3-1, IZKF/O3-4, IZKF/O3-3]
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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 CcnEl 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.
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