PIDDosome-induced p53-dependent ploidy restriction facilitates hepatocarcinogenesis

Valentina C Sladky, Katja Knapp, Tamas G Szabo, Vincent Z Braun, Laura Bongiovanni, Hilda van den Bos, Diana Cj Spierings, Bart Westendorp, Ana Curinha, Tatjana Stojakovic, Hubert Scharnagl, Gerald Timelthaler, Kaoru Tsuchia, Matthias Pinter, Georg Semmler, Floris Foijer, Alain de Bruin, Thomas Reiberger, Nataliya Rohr-Udilova, Andreas Villunger

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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. 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.

Original languageEnglish
Article number50893
Number of pages16
JournalEmbo Reports
Volume21
Issue number12
Early online date23-Nov-2020
DOIs
Publication statusPublished - 3-Dec-2020

Keywords

  • caspase&#8208
  • 2
  • hepatocellular carcinoma
  • p53
  • PIDD1
  • polyploidy
  • CENTROSOME AMPLIFICATION
  • HEPATOCYTE PLOIDY
  • TUMOR SUPPRESSION
  • CASPASE-2
  • APOPTOSIS
  • CANCER
  • POLYPLOIDIZATION
  • TUMORIGENESIS
  • ACTIVATION
  • ANEUPLOIDY

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