Ccne1 Overexpression Causes Chromosome Instability in Liver Cells and Liver Tumor Development in Mice
Autor: | Bart van de Sluis, Grace G. Nelson, Sameh A. Youssef, Erin Hurley, Raul O. Fierro Velasco, Ines Sturmlechner, Alain de Bruin, Jazeel F. Limzerwala, Janine H. van Ree, Gregory J. Gores, Daniel R. O'Brien, Erik Jan van Deursen, Lewis R. Roberts, Floris Foijer, Hilda van den Bos, Jean Pierre A. Kocher, Steve F. Bronk, Cheng Zhang, Khaled Aziz, Hu Li, Diana C.J. Spierings, Karthik B. Jeganathan, Jan M. van Deursen |
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Přispěvatelé: | Stem Cell Aging Leukemia and Lymphoma (SALL), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Center for Liver, Digestive and Metabolic Diseases (CLDM), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), dPB RMSC, LS Pathobiologie |
Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Cyclin E KINASE-INDEPENDENT FUNCTION Aneuploidy medicine.disease_cause Mice Liver Neoplasms Experimental 0302 clinical medicine Parvovirinae Chromosome instability CYCLIN-E HBV OXIDATIVE STRESS MUTATION Cyclin Oncogene Proteins Liver Neoplasms Gastroenterology Dependovirus Chromosome Structures Liver Chromosome Integrity AAV2 S Phase Cell Cycle Checkpoints 030211 gastroenterology & hepatology DNA Replication EXPRESSION Hepatocarcinogenesis Carcinoma Hepatocellular Biology Article Adenoma Liver Cell Parvoviridae Infections Polyploidy 03 medical and health sciences MOVEMENT Hepatitis B Chronic COMPENSATORY PROLIFERATION Chromosomal Instability medicine TUMORIGENESIS Animals P53 Hepatology Fibroblasts HCCS medicine.disease CENTROSOMES Cyclin E1 030104 developmental biology Cancer cell Hepatocytes Cancer research Carcinogenesis DNA Damage |
Zdroj: | Gastroenterology, 157(1). W B SAUNDERS CO-ELSEVIER INC Gastroenterology, 157(1), 210. W.B. Saunders Ltd Gastroenterology |
ISSN: | 0016-5085 |
Popis: | BACKGROUND & AIMS: The CCNE1 locus, which encodes cyclin E1, is amplified in many types of cancer cells and is activated in hepatocellular carcinomas (HCCs) from patients infected with hepatitis B virus or adeno-associated virus type 2, due to integration of the virus nearby. We investigated cell cycle and oncogenic effects of cyclin E1 overexpression in tissues of mice.METHODS: We generated mice with doxycycline-inducible expression of Ccne1 (Ccne1T mice) and activated overexpression of cyclin E1 from age 3 weeks onwards. At 14 months of age, livers were collected from mice that overexpress cyclin E1 and non-transgenic mice (controls) and analyzed for tumor burden and by histology. Mouse embryonic fibroblasts (MEFs) and hepatocytes from Ccne1T and control mice were analyzed to determine the extent to which cyclin E1 overexpression perturbs S-phase entry, DNA replication, and numbers and structures of chromosomes. Tissues from 4-month-old Ccne1T and control mice (at that age were free of tumors) were analyzed for chromosome alterations, to investigate the mechanisms by which cyclin E1 predisposes hepatocytes to transformation.RESULTS: Ccne1T mice developed more hepatocellular adenomas and HCCs than control mice. Tumors developed only in livers of Ccne1T mice, despite high levels of cyclin E1 in other tissues. Ccne1T MEFs had defects that promoted chromosome missegregation and aneuploidy, including incomplete replication of DNA, centrosome amplification, and formation of non-perpendicular mitotic spindles. Whereas Ccne1T mice accumulated near-diploid aneuploid cells in multiple tissues and organs, polyploidization was observed only in hepatocytes, with losses and gains of whole chromosomes, DNA damage, and oxidative stress.CONCLUSIONS: Livers, but not other tissues of mice with inducible overexpression of cyclin E1, develop tumors. More hepatocytes from the cyclin E1-overexpressing mice were polyploid than from control mice, and had losses or gains of whole chromosomes, DNA damage, and oxidative stress - all of these have been observed in human HCC cells. The increased risk of HCC in patients with hepatitis B virus or adeno-associated virus type 2 infection might involve activation of cyclin E1 and its effects on chromosomes and genomes of liver cells. |
Databáze: | OpenAIRE |
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