The Polyploid State Plays a Tumor-Suppressive Role in the Liver

Abstract

Most cells in the liver are polyploid, but the functional role of polyploidy is unknown. Polyploidization occurs through cytokinesis failure and endoreduplication around the time of weaning. To interrogate polyploidy while avoiding irreversible manipulations of essential cell-cycle genes, we developed orthogonal mouse models to transiently and potently alter liver ploidy. Premature weaning, as well as knockdown of E2f8 or Anln, allowed us to toggle between diploid and polyploid states. While there was no detectable impact of ploidy alterations on liver function, metabolism, or regeneration, mice with more polyploid hepatocytes suppressed tumorigenesis and mice with more diploid hepatocytes accelerated tumorigenesis in mutagen- and high-fat-induced models. Mechanistically, the diploid state was more susceptible to Cas9-mediated tumor-suppressor loss but was similarly susceptible to MYC oncogene activation, indicating that polyploidy differentially protected the liver from distinct genomic aberrations. This suggests that polyploidy evolved in part to prevent malignant outcomes of liver injury.

The Polyploid State Restricts Hepatocyte Proliferation and Liver Regeneration in Mice

“…E). Together, these data are consistent with other reports and show that LKO mice are highly susceptible to DEN/PB‐mediated tumorigenesis, suggesting that the hepatic polyploid state protects the liver from tumor formation.…”

“…LKO mice are enriched with the most proliferative cells (diploids), and, upon tumor initiation, the large numbers of rapidly cycling diploid hepatocytes in LKO mice drive tumorigenesis. A third mechanism was recently described by Zhang et al, where they showed that polyploid hepatocytes protect from liver cancer . In a series of elegant experiments, polyploid hepatocytes were found to “buffer” against loss of tumor suppressors.…”

“…B,C) were comparable . Additionally, gene signatures were equivalent between LKO and control mice at 3 and 16 weeks of age (e.g., gene ontology categories, cell cycle, metabolism, proliferation, and differentiation) and in livers depleted of E2f8 alone (e.g., differentiation genes such as Albumin , forkhead box protein 3, and hepatocyte nuclear factor 4 alpha; cytochrome P450 family members; and cell‐cycle genes) . To assess liver function following chronic injury, we maintained mice on a high‐fat diet for 8 weeks.…”

“…Polyploidy is a hallmark of cancer that has been shown to promote genomic instability and dysregulated gene expression, frequently leading to cellular transformation and tumorigenesis . Intriguingly, in the liver, polyploidy has been suggested to protect against tumorigenesis . Because LKO mice function normally and are predominantly diploid, these mice provided an opportunity to assess the role of polyploidy in hepatocellular carcinogenesis.…”

Tetraploidy in cancer and its possible link to aging

“…At least in yeast, polyploidization (tetraploidization) can induce beneficial mutations leading to environmental adaptation . A recent report suggested that tetraploidy in hepatocytes is rather tumor‐suppressive, indicating a complex relationship between tetraploidy and cancer.…”