Hepatocyte-specific deletion of the antiapoptotic protein myeloid cell leukemia-1 triggers proliferation and hepatocarcinogenesis in mice

• Verfasst von: Weber, Achim [VerfasserIn]
• Verfasst von: Boger, Regina [VerfasserIn]
• Verfasst von: Vick, Binje [VerfasserIn]
• Verfasst von: Urbanik, Toni [VerfasserIn]
• Verfasst von: Haybäck, Johannes [VerfasserIn]
• Verfasst von: Zoller, Stefan [VerfasserIn]
• Verfasst von: Teufel, Andreas [VerfasserIn]
• Verfasst von: Krammer, Peter H. [VerfasserIn]
• Verfasst von: Opferman, Joseph T. [VerfasserIn]
• Verfasst von: Galle, Peter R. [VerfasserIn]
• Verfasst von: Schuchmann, Marcus [VerfasserIn]
• Verfasst von: Heikenwälder, Mathias [VerfasserIn]
• Verfasst von: Schulze-Bergkamen, Henning [VerfasserIn]
• Titel: Hepatocyte-specific deletion of the antiapoptotic protein myeloid cell leukemia-1 triggers proliferation and hepatocarcinogenesis in mice
• Verf.angabe: Achim Weber, Regina Boger, Binje Vick, Toni Urbanik, Johannes Haybaeck, Stefan Zoller, Andreas Teufel, Peter H. Krammer, Joseph T. Opferman, Peter R. Galle, Marcus Schuchmann, Mathias Heikenwalder, and Henning Schulze-Bergkamen
• E-Jahr: 2010
• Jahr: 26 March 2010
• Umfang: 11 S.
• Illustrationen: Illustrationen
• Fussnoten: Gesehen am 11.10.2023
• Titel Quelle: Enthalten in: Hepatology
• Ort Quelle: [Alphen aan den Rijn] : Wolters Kluwer Health, 1981
• Jahr Quelle: 2010
• Band/Heft Quelle: 51(2010), 4 vom: Apr., Seite 1226-1236
• ISSN Quelle: 1527-3350
• DOI: doi:10.1002/hep.23479
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1861516533

Abstract

Regulation of hepatocellular apoptosis is crucial for liver homeostasis. Increased sensitivity of hepatocytes toward apoptosis results in chronic liver injury, whereas apoptosis resistance is linked to hepatocarcinogenesis and nonresponsiveness to therapy-induced cell death. Recently, we have demonstrated an essential role of the antiapoptotic Bcl-2 family member Myeloid cell leukemia-1 (Mcl-1) in hepatocyte survival. In mice lacking Mcl-1 specifically in hepatocytes (Mcl-1Δhep), spontaneous apoptosis caused severe liver damage. Here, we demonstrate that chronically increased apoptosis of hepatocytes coincides with strong hepatocyte proliferation resulting in hepatocellular carcinoma (HCC). Liver cell tumor formation was observed in >50% of Mcl-1Δhep mice already by the age of 8 months, whereas 12-month-old wild-type (wt) and heterozygous Mcl-1flox/wt mice lacked tumors. Tumors revealed a heterogenous spectrum ranging from small dysplastic nodules to HCC. The neoplastic nature of the tumors was confirmed by histology, expression of the HCC marker glutamine synthetase and chromosomal aberrations. Liver carcinogenesis in Mcl-1Δhep mice was paralleled by markedly increased levels of Survivin, an important regulator of mitosis which is selectively overexpressed in common human cancers. Conclusion: This study provides in vivo evidence that increased apoptosis of hepatocytes not only impairs liver homeostasis but is also accompanied by hepatocyte proliferation and hepatocarcinogenesis. Our findings might have implications for understanding apoptosis-related human liver diseases. (HEPATOLOGY 2010.)