Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Sladky, VC; Knapp, K; Szabo, TG; Braun, VZ; Bongiovanni, L; van den Bos, H; Spierings, DC; Westendorp, B; Curinha, A; Stojakovic, T; Scharnagl, H; Timelthaler, G; Tsuchia, K; Pinter, M; Semmler, G; Foijer, F; de Bruin, A; Reiberger, T; Rohr-Udilova, N; Villunger, A.
PIDDosome-induced p53-dependent ploidy restriction facilitates hepatocarcinogenesis.
EMBO Rep. 2020; 21(12):e50893-e50893
Doi: 10.15252/embr.202050893
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- Co-Autor*innen der Med Uni Graz
- Scharnagl Hubert
- Stojakovic Tatjana
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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. © 2020 The Authors. Published under the terms of the CC BY 4.0 license.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Carcinogenesis - genetics
- Carcinoma, Hepatocellular - genetics
- Humans -
- Liver Neoplasms - genetics
- Mice -
- Ploidies -
- Tumor Suppressor Protein p53 - genetics
- Find related publications in this database (Keywords)
- caspase‐ 2
- hepatocellular carcinoma
- p53
- PIDD1
- polyploidy