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.
Highlights
Hepatocellular carcinoma (HCC) represents the sixth most common cancer globally and is ranked as fourth leading cause of cancerrelated mortality, with steadily increasing incidence (Villanueva, 2019)
We used the DEN-driven model for chemically induced HCC in wt and mice lacking either Casp2, Raidd/Cradd, or Pidd1
Probing the Provisional Liver Hepatocellular Carcinoma The Cancer Genome Atlas (TCGA) data set we found that CASP2 and PIDD1 transcript levels are significantly upregulated in human HCC across all disease stages
Summary
Hepatocellular carcinoma (HCC) represents the sixth most common cancer globally and is ranked as fourth leading cause of cancerrelated mortality, with steadily increasing incidence (Villanueva, 2019). HCC almost exclusively develops on the background of chronic liver disease such as viral hepatitis or steatohepatitis and cirrhosis (Villanueva, 2019). Due to common late presentation with extensive disease, curative therapy is challenging and can only be provided by liver resection or transplantation (Sapisochin & Bruix, 2017). Liver cells are largely polyploid, a feature usually linked to chromosomal instability and subsequent aneuploidy, which is to some degree seen already in healthy hepatocytes (Knouse et al, 2014; Sladky et al, 2020). In most other cell types, polyploidy and chromosomal instability are considered to put cells at risk for malignant transformation (Ganem et al, 2007; Lens & Medema, 2019). More than one third of all human cancers is predicted to arise from tetraploid intermediates highlighting the significance of tight ploidy control (Zack et al, 2013)
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