PIDDosome-induced p53-dependent ploidy restriction facilitates hepatocarcinogenesis

Autor: Laura Bongiovanni, Kaoru Tsuchia, Tatjana Stojakovic, Katja Knapp, Vincent Zoran Braun, Hubert Scharnagl, Nataliya Rohr-Udilova, Georg Semmler, Floris Foijer, Gerald Timelthaler, Andreas Villunger, Matthias Pinter, Alain de Bruin, Tamas G. Szabo, Diana C.J. Spierings, Bart Westendorp, Valentina C. Sladky, Thomas Reiberger, Ana Curinha, Hilda van den Bos
Přispěvatelé: Pathobiologie, dPB RMSC, Dep Biomolecular Health Sciences, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Stem Cell Aging Leukemia and Lymphoma (SALL), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
caspase-2
p53
Carcinogenesis
medicine.medical_treatment
CENTROSOME AMPLIFICATION
caspase‐2
Liver transplantation
medicine.disease_cause
Biochemistry
ACTIVATION
Mice
0302 clinical medicine
Chromosome instability
PIDD1
News & Views
polyploidy
0303 health sciences
Cell Cycle
Liver Neoplasms
Articles
hepatocellular carcinoma
CANCER
3. Good health
TUMOR SUPPRESSION
APOPTOSIS
medicine.anatomical_structure
Hepatocellular carcinoma
Hepatocyte
Ploidy
Liver cancer
Signal Transduction
Carcinoma
Hepatocellular
POLYPLOIDIZATION
Biology
HEPATOCYTE PLOIDY
Article
caspase‐
03 medical and health sciences
medicine
Genetics
TUMORIGENESIS
Animals
Humans
CASPASE-2
Molecular Biology
030304 developmental biology
Ploidies
ANEUPLOIDY
medicine.disease
Centrosome
Cancer research
Tumor Suppressor Protein p53
030217 neurology & neurosurgery
Zdroj: EMBO Rep
EMBO Reports, 21, 1. Nature Publishing Group
EMBO Reports
EMBO reports
Embo Reports, 21(12):50893. Wiley
ISSN: 1469-221X
DOI: 10.15252/embr.202050893
Popis: 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.
Hepatocyte ploidy is controlled by the PIDDosome and its loss causes increased hepatocyte ploidy, which protects mice from developing liver cancer. High tumor cell density, a surrogate of low ploidy, predicts poor recurrence free survival in HCC patients.
Databáze: OpenAIRE
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