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, Yen-Lurk Lee, Pei-Chih King, Hsien-San Hou, Hao-Wen Chen, Pei-Yun Young and Hsu-Wen Chao ()
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Heng Lin: Taipei Medical University
Yen-Sung Huang: Taipei Medical University
Jean-Michel Fustin: Kyoto University
Masao Doi: Kyoto University
Huatao Chen: Northwest A&F University
Hui-Huang Lai: National Cheng Kung University
Shu-Hui Lin: Taipei Medical University
Yen-Lurk Lee: Institute of Biomedical Sciences, Academia Sinica
Pei-Chih King: Taipei Medical University
Hsien-San Hou: Institute of Biomedical Sciences, Academia Sinica
Hao-Wen Chen: Taipei Medical University
Pei-Yun Young: Taipei Medical University
Hsu-Wen Chao: Taipei Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20572-8

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