Cyclin E1 and cyclin-dependent kinase 2 are critical for initiation, but not for progression of hepatocellular carcinoma

Proceedings of the National Academy of Sciences of the United States of America
Roland SonntagChristian Liedtke

Abstract

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 elev...Continue Reading

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Citations

Sep 26, 2020·Cell Cycle·Yu ZhouPiotr Sicinski
May 10, 2020·International Journal of Molecular Sciences·Anna HübbersChristian Liedtke
Feb 5, 2021·Frontiers in Cell and Developmental Biology·Yihao LiaoNing Jiang
Dec 17, 2019·Drug Discovery Today·Solomon TadesseShudong Wang
Feb 4, 2021·Medicine·Jie JiangXinli Zhan
May 11, 2020·Seminars in Cell & Developmental Biology·Nathan Palmer, Philipp Kaldis
Apr 4, 2021·International Journal of Molecular Sciences·Paweł ŁukasikIzabela Gutowska
Apr 15, 2021·Cancer Cell International·Zahra FarzanehMaryam Farzaneh
Apr 24, 2021·Cancer Cell·Jan M SuskiPiotr Sicinski
May 11, 2021·The Journal of Pathology. Clinical Research·Solange De NoonSam Behjati
May 31, 2021·Trends in Cell Biology·Chen ChuPiotr Sicinski
Jun 25, 2021·Frontiers in Genetics·Shuying ChenYuan Lv
Jul 19, 2021·Clinical and Experimental Medicine·Yue LiXiming Xu
Oct 8, 2021·Cancer Biotherapy & Radiopharmaceuticals·Wang-Yang YeYi-Wu Dang
Oct 17, 2021·Cellular and Molecular Gastroenterology and Hepatology·Beatrice FogliaMaurizio Parola
Aug 28, 2021·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Komal RamaniShelly C Lu

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