Hyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver

Heng Lin, Yen-Sung Huang, Jean-Michel Fustin, Masao Doi, Huatao Chen, Hui-Huang Lai, Shu-Hui Lin, Pei-Chih King, Hsien-San Hou, Hao-Wen Chen, Pei-Yun Young, Hsu-Wen Chao

Research output: Contribution to journalArticlepeer-review

Abstract

Hepatocellular carcinoma (HCC) is the most predominant primary malignancy in the liver. Genotoxic and genetic models have revealed that HCC cells are derived from hepatocytes, but where the critical region for tumor foci emergence is and how this transformation occurs are still unclear. Here, hyperpolyploidization of hepatocytes around the centrilobular (CL) region is demonstrated to be closely linked with the development of HCC cells after diethylnitrosamine treatment. We identify the CL region as a dominant lobule for accumulation of hyperpolyploid hepatocytes and preneoplastic tumor foci formation. We also demonstrate that upregulation of Aurkb plays a critical role in promoting hyperpolyploidization. Increase of AURKB phosphorylation is detected on the midbody during cytokinesis, causing abscission failure and hyperpolyploidization. Pharmacological inhibition of AURKB dramatically reduces nucleus size and tumor foci number surrounding the CL region in diethylnitrosamine-treated liver. Our work reveals an intimate molecular link between pathological hyperpolyploidy of CL hepatocytes and transformation into HCC cells.

Original languageEnglish
Pages (from-to)645
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 28 Jan 2021

Keywords

  • Animals
  • Carcinoma, Hepatocellular/chemically induced
  • Cell Transformation, Neoplastic/chemically induced
  • Cells, Cultured
  • Diethylnitrosamine/toxicity
  • Female
  • Hepatocytes/drug effects
  • Humans
  • Liver/drug effects
  • Liver Neoplasms/chemically induced
  • Male
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Microscopy, Confocal
  • Polyploidy
  • Precancerous Conditions/chemically induced

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