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Hyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver.


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.

SUBMITTER: Lin H 

PROVIDER: S-EPMC7844417 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Hyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver.

Lin Heng H   Huang Yen-Sung YS   Fustin Jean-Michel JM   Doi Masao M   Chen Huatao H   Lai Hui-Huang HH   Lin Shu-Hui SH   Lee Yen-Lurk YL   King Pei-Chih PC   Hou Hsien-San HS   Chen Hao-Wen HW   Young Pei-Yun PY   Chao Hsu-Wen HW  

Nature communications 20210128 1


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  ...[more]

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