Expression of Cyclin E1 in hepatic stellate cells is critical for the induction and progression of liver fibrosis and hepatocellular carcinoma in mice
Abstract Hepatocellular carcinoma (HCC) is one of the most severe malignancies with increasing incidence and limited treatment options. Typically, HCC develops during a multistep process involving chronic liver inflammation and liver fibrosis. The latter is characterized by the accumulation of extra...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06077-4 |
| _version_ | 1797736403138772992 |
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| author | Julia Otto Anna Verwaayen Christian Penners Jana Hundertmark Cheng Lin Carina Kallen Daniela Paffen Tobias Otto Hilmar Berger Frank Tacke Ralf Weiskirchen Yulia A. Nevzorova Matthias Bartneck Christian Trautwein Roland Sonntag Christian Liedtke |
| author_facet | Julia Otto Anna Verwaayen Christian Penners Jana Hundertmark Cheng Lin Carina Kallen Daniela Paffen Tobias Otto Hilmar Berger Frank Tacke Ralf Weiskirchen Yulia A. Nevzorova Matthias Bartneck Christian Trautwein Roland Sonntag Christian Liedtke |
| author_sort | Julia Otto |
| collection | DOAJ |
| description | Abstract Hepatocellular carcinoma (HCC) is one of the most severe malignancies with increasing incidence and limited treatment options. Typically, HCC develops during a multistep process involving chronic liver inflammation and liver fibrosis. The latter is characterized by the accumulation of extracellular matrix produced by Hepatic Stellate Cells (HSCs). This process involves cell cycle re-entry and proliferation of normally quiescent HSCs in an ordered sequence that is highly regulated by cyclins and associated cyclin-dependent kinases (CDKs) such as the Cyclin E1 (CCNE1)/CDK2 kinase complex. In the present study, we examined the role of Cyclin E1 (Ccne1) and Cdk2 genes in HSCs for liver fibrogenesis and hepatocarcinogenesis. To this end, we generated conditional knockout mice lacking Ccne1 or Cdk2 specifically in HSCs (Ccne1 ∆HSC or Cdk2 ∆HSC). Ccne1 ∆HSC mice showed significantly reduced liver fibrosis formation and attenuated HSC activation in the carbon tetrachloride (CCl4) model. In a combined model of fibrosis-driven hepatocarcinogenesis, Ccne1 ∆HSC mice revealed decreased HSC activation even after long-term observation and substantially reduced tumor load in the liver when compared to wild-type controls. Importantly, the deletion of Cdk2 in HSCs also resulted in attenuated liver fibrosis after chronic CCl4 treatment. Single-cell RNA sequencing revealed that only a small fraction of HSCs expressed Ccne1/Cdk2 at a distinct time point after CCl4 treatment. In summary, we provide evidence that Ccne1 expression in a small population of HSCs is sufficient to trigger extensive liver fibrosis and hepatocarcinogenesis in a Cdk2-dependent manner. Thus, HSC-specific targeting of Ccne1 or Cdk2 in patients with liver fibrosis and high risk for HCC development could be therapeutically beneficial. |
| first_indexed | 2024-03-12T13:12:17Z |
| format | Article |
| id | doaj.art-45c433be5aaf43cdb0361d45f0a768b8 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-12T13:12:17Z |
| publishDate | 2023-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-45c433be5aaf43cdb0361d45f0a768b82023-08-27T11:30:11ZengNature Publishing GroupCell Death and Disease2041-48892023-08-0114811510.1038/s41419-023-06077-4Expression of Cyclin E1 in hepatic stellate cells is critical for the induction and progression of liver fibrosis and hepatocellular carcinoma in miceJulia Otto0Anna Verwaayen1Christian Penners2Jana Hundertmark3Cheng Lin4Carina Kallen5Daniela Paffen6Tobias Otto7Hilmar Berger8Frank Tacke9Ralf Weiskirchen10Yulia A. Nevzorova11Matthias Bartneck12Christian Trautwein13Roland Sonntag14Christian Liedtke15Department of Medicine III, University Hospital RWTH AachenDepartment of Medicine III, University Hospital RWTH AachenDepartment of Medicine III, University Hospital RWTH AachenCharité - Universitätsmedizin Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité MitteDepartment of Medicine III, University Hospital RWTH AachenDepartment of Medicine III, University Hospital RWTH AachenDepartment of Medicine III, University Hospital RWTH AachenDepartment of Medicine III, University Hospital RWTH AachenCharité - Universitätsmedizin Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité MitteCharité - Universitätsmedizin Berlin, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité MitteInstitute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), University Hospital RWTH AachenDepartment of Immunology, Ophthalmology and ENT, Complutense University School of MedicineDepartment of Medicine III, University Hospital RWTH AachenDepartment of Medicine III, University Hospital RWTH AachenDepartment of Medicine III, University Hospital RWTH AachenDepartment of Medicine III, University Hospital RWTH AachenAbstract Hepatocellular carcinoma (HCC) is one of the most severe malignancies with increasing incidence and limited treatment options. Typically, HCC develops during a multistep process involving chronic liver inflammation and liver fibrosis. The latter is characterized by the accumulation of extracellular matrix produced by Hepatic Stellate Cells (HSCs). This process involves cell cycle re-entry and proliferation of normally quiescent HSCs in an ordered sequence that is highly regulated by cyclins and associated cyclin-dependent kinases (CDKs) such as the Cyclin E1 (CCNE1)/CDK2 kinase complex. In the present study, we examined the role of Cyclin E1 (Ccne1) and Cdk2 genes in HSCs for liver fibrogenesis and hepatocarcinogenesis. To this end, we generated conditional knockout mice lacking Ccne1 or Cdk2 specifically in HSCs (Ccne1 ∆HSC or Cdk2 ∆HSC). Ccne1 ∆HSC mice showed significantly reduced liver fibrosis formation and attenuated HSC activation in the carbon tetrachloride (CCl4) model. In a combined model of fibrosis-driven hepatocarcinogenesis, Ccne1 ∆HSC mice revealed decreased HSC activation even after long-term observation and substantially reduced tumor load in the liver when compared to wild-type controls. Importantly, the deletion of Cdk2 in HSCs also resulted in attenuated liver fibrosis after chronic CCl4 treatment. Single-cell RNA sequencing revealed that only a small fraction of HSCs expressed Ccne1/Cdk2 at a distinct time point after CCl4 treatment. In summary, we provide evidence that Ccne1 expression in a small population of HSCs is sufficient to trigger extensive liver fibrosis and hepatocarcinogenesis in a Cdk2-dependent manner. Thus, HSC-specific targeting of Ccne1 or Cdk2 in patients with liver fibrosis and high risk for HCC development could be therapeutically beneficial.https://doi.org/10.1038/s41419-023-06077-4 |
| spellingShingle | Julia Otto Anna Verwaayen Christian Penners Jana Hundertmark Cheng Lin Carina Kallen Daniela Paffen Tobias Otto Hilmar Berger Frank Tacke Ralf Weiskirchen Yulia A. Nevzorova Matthias Bartneck Christian Trautwein Roland Sonntag Christian Liedtke Expression of Cyclin E1 in hepatic stellate cells is critical for the induction and progression of liver fibrosis and hepatocellular carcinoma in mice Cell Death and Disease |
| title | Expression of Cyclin E1 in hepatic stellate cells is critical for the induction and progression of liver fibrosis and hepatocellular carcinoma in mice |
| title_full | Expression of Cyclin E1 in hepatic stellate cells is critical for the induction and progression of liver fibrosis and hepatocellular carcinoma in mice |
| title_fullStr | Expression of Cyclin E1 in hepatic stellate cells is critical for the induction and progression of liver fibrosis and hepatocellular carcinoma in mice |
| title_full_unstemmed | Expression of Cyclin E1 in hepatic stellate cells is critical for the induction and progression of liver fibrosis and hepatocellular carcinoma in mice |
| title_short | Expression of Cyclin E1 in hepatic stellate cells is critical for the induction and progression of liver fibrosis and hepatocellular carcinoma in mice |
| title_sort | expression of cyclin e1 in hepatic stellate cells is critical for the induction and progression of liver fibrosis and hepatocellular carcinoma in mice |
| url | https://doi.org/10.1038/s41419-023-06077-4 |
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