PIDDosome-induced p53-dependent ploidy restriction facilitates hepatocarcinogenesis.

Autor: Sladky VC; Institute of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria., Knapp K; Institute of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria., Szabo TG; Institute of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria., Braun VZ; Institute of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria., Bongiovanni L; Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands., van den Bos H; European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands., Spierings DC; European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands., Westendorp B; Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands., Curinha A; Institute of Pathophysiology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria., Stojakovic T; Clinical Institute of Medical and Chemical Laboratory Diagnostics, University Hospital Graz, Graz, Austria., Scharnagl H; Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria., Timelthaler G; Institute for Cancer Research, Internal Medicine I, Medical University of Vienna, Vienna, Austria., Tsuchia K; Department of Gastroenterology & Hepatology, Musashino Red Cross Hospital, Tokyo, Japan., Pinter M; Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria., Semmler G; Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria., Foijer F; European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands., de Bruin A; Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.; Department Pediatrics, University Medical Center Groningen, University Groningen, Groningen, The Netherlands., Reiberger T; Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Rohr-Udilova N; Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria., Villunger A; Institute of Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Jazyk: angličtina
Zdroj: EMBO reports [EMBO Rep] 2020 Dec 03; Vol. 21 (12), pp. e50893. Date of Electronic Publication: 2020 Nov 23.
DOI: 10.15252/embr.202050893
Abstrakt: Polyploidization frequently precedes tumorigenesis but also occurs during normal development in several tissues. Hepatocyte ploidy is controlled by the PIDDosome during development and regeneration. This multi-protein complex is activated by supernumerary centrosomes to induce p53 and restrict proliferation of polyploid cells, otherwise prone for chromosomal instability. PIDDosome deficiency in the liver results in drastically increased polyploidy. To investigate PIDDosome-induced p53-activation in the pathogenesis of liver cancer, we chemically induced hepatocellular carcinoma (HCC) in mice. Strikingly, PIDDosome deficiency reduced tumor number and burden, despite the inability to activate p53 in polyploid cells. Liver tumors arise primarily from cells with low ploidy, indicating an intrinsic pro-tumorigenic effect of PIDDosome-mediated ploidy restriction. These data suggest that hyperpolyploidization caused by PIDDosome deficiency protects from HCC. Moreover, high tumor cell density, as a surrogate marker of low ploidy, predicts poor survival of HCC patients receiving liver transplantation. Together, we show that the PIDDosome is a potential therapeutic target to manipulate hepatocyte polyploidization for HCC prevention and that tumor cell density may serve as a novel prognostic marker for recurrence-free survival in HCC patients.
(© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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