Hepatic Loss of Borealin Impairs Postnatal Liver Development, Regeneration, and Hepatocarcinogenesis

J Biol Chem. 2016 Sep 30;291(40):21137-21147. doi: 10.1074/jbc.M116.736173. Epub 2016 Aug 19.

Abstract

Borealin, a member of the chromosomal passenger complex, plays a key regulatory role at centromeres and the central spindle during mitosis. Loss of Borealin leads to defective cell proliferation and early embryonic lethality. The in vivo functions of Borealin in mammalian postnatal development, tissue homeostasis, and tumorigenesis remain elusive. We specifically analyzed the role of Borealin in regulating postnatal liver development, damage-induced liver regeneration, and liver carcinogenesis using mice carrying conditional Borealin alleles. Perinatal loss of Borealin caused increased genome ploidy and enlarged cell size in hepatocytes, likely due to the impaired function of the chromosomal passenger complex in mitosis. Borealin deletion also showed attenuated expansion of Sox9+HNF4α+ progenitor-like cells in liver regeneration during 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet-induced liver injury. Moreover, ΔN90-β-Catenin and c-Met-induced hepatocarcinogenesis development was largely impeded by Borealin deletion. These findings indicate that Borealin plays a key role in liver development, regeneration, and tumorigenesis and suggests that Borealin could be a potential target for related liver diseases.

Keywords: Borealin; cell cycle; hepatocellular carcinoma; liver cancer; liver development; liver injury; liver progenitor-like cell; stem cells.

MeSH terms

  • Animals
  • Cell Cycle Proteins / deficiency*
  • Cell Cycle Proteins / metabolism
  • Cell Size
  • Chromosomal Proteins, Non-Histone / deficiency*
  • Chromosomal Proteins, Non-Histone / metabolism
  • Hepatocyte Nuclear Factor 4 / genetics
  • Hepatocyte Nuclear Factor 4 / metabolism
  • Hepatocytes / metabolism*
  • Hepatocytes / pathology
  • Liver / metabolism*
  • Liver / pathology
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Liver Regeneration*
  • Mice
  • Mice, Mutant Strains
  • Ploidies
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism
  • Stem Cells / metabolism*
  • Stem Cells / pathology

Substances

  • CDCA8 protein, mouse
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Hepatocyte Nuclear Factor 4
  • Hnf4a protein, mouse
  • SOX9 Transcription Factor
  • Sox9 protein, mouse
  • Proto-Oncogene Proteins c-met