PIDDosome-induced p53-activation for ploidy restriction facilitates hepatocarcinogenesis
PIDDosome-induced p53-activation for ploidy restriction facilitates hepatocarcinogenesis
Abstract Polyploidization frequently precedes tumorigenesis but also occurs during normal development in several tissues. Hepatocyte ploidy is controlled by the PIDDosome during development and regeneration. The PIDDosome 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 of 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 tumor cell density serves as a novel prognostic marker for recurrence free survival in HCC patients.
Bongiovanni Laura、Sladky Valentina、Timelthaler Gerald、Pinter Matthias、Tsuchia Kaoru、Foijer Floris、Reiberger Thomas、Stojakovic Tatjana、Scharnagl Hubert、de Bruin Alain、Rohr-Udilova Nataliya、van den Bos Hilda、Villunger Andreas、Westendorp Bart、Szabo Tamas G.、Knapp Katja、Spierings Diana C.J.
Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht UniversityDivision of Developmental Immunology, Biocenter, Medical University of InnsbruckInstitute for Cancer Research, Internal Medicine I, Medical University of ViennaDivision of Gastroenterology and Hepatology, Department of Medicine III, Medical University of ViennaMusashino Red Cross Hospital, Dept. of Gastroenterology & HepatologyEuropean Research Institute for the Biology of Ageing, University of Groningen, University Medical Center GroningenDivision of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna||Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD)||CeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesUniversity Hospital Graz, Clinical Institute of Medical and Chemical Laboratory DiagnosticsMedical University of Graz, Clinical Institute of Medical and Chemical Laboratory DiagnosticsDepartment of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University||Department Pediatrics, University Medical Center Groningen, University GroningenDivision of Gastroenterology and Hepatology, Department of Medicine III, Medical University of ViennaEuropean Research Institute for the Biology of Ageing, University of Groningen, University Medical Center GroningenDivision of Developmental Immunology, Biocenter, Medical University of Innsbruck||Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD)||CeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesDepartment of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht UniversityDivision of Developmental Immunology, Biocenter, Medical University of InnsbruckDivision of Developmental Immunology, Biocenter, Medical University of InnsbruckEuropean Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen
肿瘤学基础医学分子生物学
Caspase-2PIDD1p53polyploidyHCC
Bongiovanni Laura,Sladky Valentina,Timelthaler Gerald,Pinter Matthias,Tsuchia Kaoru,Foijer Floris,Reiberger Thomas,Stojakovic Tatjana,Scharnagl Hubert,de Bruin Alain,Rohr-Udilova Nataliya,van den Bos Hilda,Villunger Andreas,Westendorp Bart,Szabo Tamas G.,Knapp Katja,Spierings Diana C.J..PIDDosome-induced p53-activation for ploidy restriction facilitates hepatocarcinogenesis[EB/OL].(2025-03-28)[2025-06-01].https://www.biorxiv.org/content/10.1101/2020.05.13.092486.点此复制
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