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

doi:10.1038/s41467-020-20572-8

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

Division of Integrative Physiology

Taipei Medical University
Kyoto University
Northwest University
National Cheng Kung University
Biomedical Sciences Institute

Research output: Contribution to journal › Article › peer-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 language	English
Pages (from-to)	645
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20572-8
Publication status	Published - 28 Jan 2021

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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

Access to Document

10.1038/s41467-020-20572-8Licence: CC BY

1 Not started
1 Active

Methylation of mRNA as a Coupling Mechanism Between Diet, Metabolism and the Circadian Clock.
Fustin, J.-M. (PI)
2/03/20 → 1/03/27
Project: Research
Centre for Biological Timing
Lucas, R. (PI), Bechtold, D. (PI), Fustin, J.-M. (PI), Ashe, H. (PI), Brown, T. (PI), Blaikley, J. (PI), Brass, A. (PI), Chandola, T. (PI), Durrington, H. (PI), Else, K. (PI), Hepworth, M. (PI), Hunter, L. (PI), Kadler, K. (PI), Kitchen, G. (PI), Loudon, A. (PI), Macdonald, A. (PI), Mcbeth, J. (PI), Milosavljevic, N. (PI), Rattray, M. (PI), Rutter, M. (PI), Sharrocks, A. (PI), Spiller, D. (PI), Storchi, R. (PI), Belle, M. (PI), Meng, Q.-J. (PI), Allen, A. (PI), Dixon, W. (PI), Gibbs, J. (PI), Hazel, A. (PI), Papalopulu, N. (PI), Ray, D. (PI), White, M. (PI), Chang, J. (PI), Bano Otalora, B. (CoI), Zavala, E. (PI), Orlowska-Feuer, P. (PI) & Didikoglu, A. (PI)
Project: Research

Cite this

@article{de1f8094ba834a54b9a130d73f35f0ef,

title = "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.",

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",

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

year = "2021",

month = jan,

day = "28",

doi = "10.1038/s41467-020-20572-8",

language = "English",

volume = "12",

pages = "645",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

TY - JOUR

T1 - Hyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver

AU - Lin, Heng

AU - Huang, Yen-Sung

AU - Fustin, Jean-Michel

AU - Doi, Masao

AU - Chen, Huatao

AU - Lai, Hui-Huang

AU - Lin, Shu-Hui

AU - King, Pei-Chih

AU - Hou, Hsien-San

AU - Chen, Hao-Wen

AU - Young, Pei-Yun

AU - Chao, Hsu-Wen

PY - 2021/1/28

Y1 - 2021/1/28

N2 - 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.

AB - 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.

KW - Animals

KW - Carcinoma, Hepatocellular/chemically induced

KW - Cell Transformation, Neoplastic/chemically induced

KW - Cells, Cultured

KW - Diethylnitrosamine/toxicity

KW - Female

KW - Hepatocytes/drug effects

KW - Humans

KW - Liver/drug effects

KW - Liver Neoplasms/chemically induced

KW - Male

KW - Mice, Inbred C57BL

KW - Mice, Inbred ICR

KW - Mice, Inbred NOD

KW - Mice, Knockout

KW - Mice, SCID

KW - Microscopy, Confocal

KW - Polyploidy

KW - Precancerous Conditions/chemically induced

U2 - 10.1038/s41467-020-20572-8

DO - 10.1038/s41467-020-20572-8

M3 - Article

C2 - 33510150

SN - 2041-1723

VL - 12

SP - 645

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

Hyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver

Abstract

UN SDGs

Keywords

Access to Document

Fingerprint

Projects

Methylation of mRNA as a Coupling Mechanism Between Diet, Metabolism and the Circadian Clock.

Centre for Biological Timing

Cite this