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

Dev Cell. 2018 Feb 26;44(4):447-459.e5. doi: 10.1016/j.devcel.2018.01.010. Epub 2018 Feb 8.


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.

Keywords: Anln; E2f8; cytokinesis; hepatocellular carcinoma; liver cancer; mouse model; polyploidy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology*
  • Cytokinesis / physiology
  • Female
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Liver / metabolism
  • Liver / pathology*
  • Liver Neoplasms, Experimental / genetics
  • Liver Neoplasms, Experimental / metabolism
  • Liver Neoplasms, Experimental / pathology*
  • Liver Regeneration / physiology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, Knockout
  • Microfilament Proteins / physiology*
  • Polyploidy*
  • Repressor Proteins / physiology*


  • Anln protein, mouse
  • E2F8 protein, mouse
  • Microfilament Proteins
  • Repressor Proteins