Cyclin E1 in Murine and Human Liver Cancer: A Promising Target for Therapeutic Intervention during Tumour Progression

Cyclin E1 (CCNE1) is a regulatory subunit of Cyclin-dependent kinase 2 (CDK2) and is thought to control the transition of quiescent cells into cell cycle progression. Recently, we identified CCNE1 and CDK2 as key factors for the initiation of hepatocellular carcinoma (HCC). In the present study, we...

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Autores principales:	Roland Sonntag, Christian Penners, Marlene Kohlhepp, Ute Haas, Daniela Lambertz, Andreas Kroh, Thorsten Cramer, Fabio Ticconi, Ivan G. Costa, Frank Tacke, Nikolaus Gassler, Christian Trautwein, Christian Liedtke
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cell cycle cancer stem cell microenvironment microinvasion DNA integrity Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/f1b7e5a6281046dcb9a3bcb739e2f045
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spelling	oai:doaj.org-article:f1b7e5a6281046dcb9a3bcb739e2f0452021-11-25T17:02:35ZCyclin E1 in Murine and Human Liver Cancer: A Promising Target for Therapeutic Intervention during Tumour Progression10.3390/cancers132256802072-6694https://doaj.org/article/f1b7e5a6281046dcb9a3bcb739e2f0452021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5680https://doaj.org/toc/2072-6694Cyclin E1 (CCNE1) is a regulatory subunit of Cyclin-dependent kinase 2 (CDK2) and is thought to control the transition of quiescent cells into cell cycle progression. Recently, we identified CCNE1 and CDK2 as key factors for the initiation of hepatocellular carcinoma (HCC). In the present study, we dissected the contributions of CCNE1 and CDK2 for HCC progression in mice and patients. Therefore, we generated genetically modified mice allowing inducible deletion of <i>Ccne1</i> or <i>Cdk2</i>. After initiation of HCC, using the hepatocarcinogen diethylnitrosamine (DEN), we deleted <i>Ccne1</i> or <i>Cdk2</i> and subsequently analysed HCC progression. The relevance of CCNE1 or CDK2 for human HCC progression was investigated by in silico database analysis. Interventional deletion of <i>Ccne1</i>, but not of <i>Cdk2</i>, substantially reduced the HCC burden in mice. <i>Ccne1</i>-deficient HCCs were characterised by attenuated proliferation, impaired DNA damage response and downregulation of markers for stemness and microinvasion. Additionally, the tumour microenvironment of <i>Ccne1</i>-deficient mice showed a reduction in immune mediators, myeloid cells and cancer-associated fibroblasts. In sharp contrast, <i>Cdk2</i> was dispensable for HCC progression in mice. In agreement with our mouse data, <i>CCNE1</i> was overexpressed in HCC patients independent of risk factors, and associated with reduced disease-free survival, a common signature for enhanced chromosomal instability, proliferation, dedifferentiation and invasion. However, <i>CDK2</i> lacked diagnostic or prognostic value in HCC patients. In summary, CCNE1 drives HCC progression in a CDK2-independent manner in mice and man. Therefore, interventional inactivation of CCNE1 represents a promising strategy the treatment of liver cancer.Roland SonntagChristian PennersMarlene KohlheppUte HaasDaniela LambertzAndreas KrohThorsten CramerFabio TicconiIvan G. CostaFrank TackeNikolaus GasslerChristian TrautweinChristian LiedtkeMDPI AGarticlecell cyclecancer stem cellmicroenvironmentmicroinvasionDNA integrityNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5680, p 5680 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cell cycle cancer stem cell microenvironment microinvasion DNA integrity Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	cell cycle cancer stem cell microenvironment microinvasion DNA integrity Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Roland Sonntag Christian Penners Marlene Kohlhepp Ute Haas Daniela Lambertz Andreas Kroh Thorsten Cramer Fabio Ticconi Ivan G. Costa Frank Tacke Nikolaus Gassler Christian Trautwein Christian Liedtke Cyclin E1 in Murine and Human Liver Cancer: A Promising Target for Therapeutic Intervention during Tumour Progression
description	Cyclin E1 (CCNE1) is a regulatory subunit of Cyclin-dependent kinase 2 (CDK2) and is thought to control the transition of quiescent cells into cell cycle progression. Recently, we identified CCNE1 and CDK2 as key factors for the initiation of hepatocellular carcinoma (HCC). In the present study, we dissected the contributions of CCNE1 and CDK2 for HCC progression in mice and patients. Therefore, we generated genetically modified mice allowing inducible deletion of <i>Ccne1</i> or <i>Cdk2</i>. After initiation of HCC, using the hepatocarcinogen diethylnitrosamine (DEN), we deleted <i>Ccne1</i> or <i>Cdk2</i> and subsequently analysed HCC progression. The relevance of CCNE1 or CDK2 for human HCC progression was investigated by in silico database analysis. Interventional deletion of <i>Ccne1</i>, but not of <i>Cdk2</i>, substantially reduced the HCC burden in mice. <i>Ccne1</i>-deficient HCCs were characterised by attenuated proliferation, impaired DNA damage response and downregulation of markers for stemness and microinvasion. Additionally, the tumour microenvironment of <i>Ccne1</i>-deficient mice showed a reduction in immune mediators, myeloid cells and cancer-associated fibroblasts. In sharp contrast, <i>Cdk2</i> was dispensable for HCC progression in mice. In agreement with our mouse data, <i>CCNE1</i> was overexpressed in HCC patients independent of risk factors, and associated with reduced disease-free survival, a common signature for enhanced chromosomal instability, proliferation, dedifferentiation and invasion. However, <i>CDK2</i> lacked diagnostic or prognostic value in HCC patients. In summary, CCNE1 drives HCC progression in a CDK2-independent manner in mice and man. Therefore, interventional inactivation of CCNE1 represents a promising strategy the treatment of liver cancer.
format	article
author	Roland Sonntag Christian Penners Marlene Kohlhepp Ute Haas Daniela Lambertz Andreas Kroh Thorsten Cramer Fabio Ticconi Ivan G. Costa Frank Tacke Nikolaus Gassler Christian Trautwein Christian Liedtke
author_facet	Roland Sonntag Christian Penners Marlene Kohlhepp Ute Haas Daniela Lambertz Andreas Kroh Thorsten Cramer Fabio Ticconi Ivan G. Costa Frank Tacke Nikolaus Gassler Christian Trautwein Christian Liedtke
author_sort	Roland Sonntag
title	Cyclin E1 in Murine and Human Liver Cancer: A Promising Target for Therapeutic Intervention during Tumour Progression
title_short	Cyclin E1 in Murine and Human Liver Cancer: A Promising Target for Therapeutic Intervention during Tumour Progression
title_full	Cyclin E1 in Murine and Human Liver Cancer: A Promising Target for Therapeutic Intervention during Tumour Progression
title_fullStr	Cyclin E1 in Murine and Human Liver Cancer: A Promising Target for Therapeutic Intervention during Tumour Progression
title_full_unstemmed	Cyclin E1 in Murine and Human Liver Cancer: A Promising Target for Therapeutic Intervention during Tumour Progression
title_sort	cyclin e1 in murine and human liver cancer: a promising target for therapeutic intervention during tumour progression
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/f1b7e5a6281046dcb9a3bcb739e2f045
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Cyclin E1 in Murine and Human Liver Cancer: A Promising Target for Therapeutic Intervention during Tumour Progression

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