Arid1a deficiency promotes hepatocyte hyperpolyploidy and drives intrahepatic cholangiocarcinoma in mice

Qi Bian; Shu Wang; Zimin Song; Fang Liu; Muqing Cao; Nan Yang; Jun Ying; Jia-Syuan Hu; Xinyuan Xiong; Huiqin Zhu; Jun Wu; Jie Yang; Xiaonan Wang; Shunli Shen; Xuxu Sun

doi:10.1097/HEP.0000000000001422

Arid1a deficiency promotes hepatocyte hyperpolyploidy and drives intrahepatic cholangiocarcinoma in mice

Hepatology. 2025 Jun 9. doi: 10.1097/HEP.0000000000001422. Online ahead of print.

Authors

Qi Bian^{1

2}, Shu Wang¹, Zimin Song³, Fang Liu¹, Muqing Cao⁴, Nan Yang¹, Jun Ying⁵, Jia-Syuan Hu^{1

6}, Xinyuan Xiong¹, Huiqin Zhu¹, Jun Wu², Jie Yang¹, Xiaonan Wang⁵, Shunli Shen³, Xuxu Sun^{1

2}

Affiliations

¹ Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Department of Laboratory Medicine, Jiading Branch of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Hepatic Surgery, Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
⁴ Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵ School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ Shanghai High School International Division, Shanghai, China.

PMID: 40489743
DOI: 10.1097/HEP.0000000000001422

Abstract

Background and aims: Intrahepatic cholangiocarcinomas (ICCs) are aggressive liver tumors with high heterogeneity and limited therapeutic options. Although traditionally thought to arise from biliary cells, recent findings suggest that hepatocytes may also serve as a cellular origin for ICC. However, the mechanisms underlying hepatocyte malignant transformation and ICC initiation remain poorly understood.

Approach and results: We employed oncogene-driven and chemically induced ICC murine models, along with cellular models, to recapitulate the transformation of hepatocytes into ICC. Our findings demonstrate that mature hepatocytes undergo a significant hyperpolyploid state during ICC initiation. Hyperpolyploidy promotes aberrant cell division and chromosomal instability, accelerating hepatocyte transformation and ICC onset. Furthermore, we identified the chromatin remodeling factor Arid1a as a critical suppressor of hyperpolyploidy. Arid1a deficiency disrupts mitotic machinery at the centrosome, driving hyperpolyploidization and ICC tumorigenesis.

Conclusions: Hepatocytes can transform into ICC through a process involving hyperpolyploidization. This study offers new insights into the pathogenesis of ICC, particularly in patients harboring frequent ARID1A mutations.

Keywords: SWI/SNF; intrahepatic cholangiocarcinoma; polyploidy.