Unknown

Dataset Information

0

PIDDosome-induced p53-dependent 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. 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.

SUBMITTER: Dr. Valentina, C Sladky 

PROVIDER: S-SCDT-EMBOR-2020-50893-T | biostudies-other |

REPOSITORIES: biostudies-other

Similar Datasets

| S-EPMC7726793 | biostudies-literature
| S-EPMC4753255 | biostudies-literature
| S-EPMC7652937 | biostudies-literature
| S-EPMC3164924 | biostudies-other
| S-EPMC3237853 | biostudies-literature
| S-EPMC3855850 | biostudies-literature
| S-EPMC3805120 | biostudies-literature
| S-EPMC1217768 | biostudies-other
| S-EPMC6966430 | biostudies-literature
| S-EPMC7000409 | biostudies-literature