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

Shuyuan Zhang, Kejin Zhou, Xin Luo, Lin Li, Ho Chou Tu, Alfica Sehgal, Liem H. Nguyen, Yu Zhang, Purva Gopal, Branden D. Tarlow, Daniel J. Siegwart, Hao Zhu

Research output: Contribution to journalArticle

36 Scopus citations

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. Most liver cells are polyploid, but the functional role of wholesale genome duplications is unknown. To interrogate liver polyploidy function without irreversible manipulations of cell-cycle genes, Zhang et al. developed models to transiently alter ploidy, finding that polyploidy reduces tumor development by buffering against tumor-suppressor loss of heterozygosity.

Original languageEnglish (US)
JournalDevelopmental Cell
DOIs
StateAccepted/In press - Jan 1 2018

Keywords

  • Anln
  • Cytokinesis
  • E2f8
  • Hepatocellular carcinoma
  • Liver cancer
  • Mouse model
  • Polyploidy

ASJC Scopus subject areas

  • Developmental Biology

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  • Cite this

    Zhang, S., Zhou, K., Luo, X., Li, L., Tu, H. C., Sehgal, A., Nguyen, L. H., Zhang, Y., Gopal, P., Tarlow, B. D., Siegwart, D. J., & Zhu, H. (Accepted/In press). The Polyploid State Plays a Tumor-Suppressive Role in the Liver. Developmental Cell. https://doi.org/10.1016/j.devcel.2018.01.010