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

Arid1a deficiency promotes hepatocyte hyperpolyploidy and drives intrahepatic cholangiocarcinoma in mice

Qi Bian  1   2 , Shu Wang  1 , Zimin Song  3 , Fang Liu  1 , Muqing Cao  4 , Nan Yang  1 , Jun Ying  5 , Jia-Syuan Hu  1   6 , Xinyuan Xiong  1 , Huiqin Zhu  1 , Jun Wu  2 , Jie Yang  1 , Xiaonan Wang  5 , Shunli Shen  3 , Xuxu Sun  1   2
Affiliations

Arid1a deficiency promotes hepatocyte hyperpolyploidy and drives intrahepatic cholangiocarcinoma in mice

Qi Bian et al. Hepatology. .

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.

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References

    1. Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan SA, Roberts LR, et al. Cholangiocarcinoma 2020: The next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020;17:557–588.
    1. Ilyas SI, Gores GJ. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology. 2013;145:1215–1229.
    1. Marquardt JU, Andersen JB, Thorgeirsson SS. Functional and genetic deconstruction of the cellular origin in liver cancer. Nat Rev Cancer. 2015;15:653–667.
    1. Wardell CP, Fujita M, Yamada T, Simbolo M, Fassan M, Karlic R, et al. Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations. J Hepatol. 2018;68:959–969.
    1. Fan B, Malato Y, Calvisi DF, Naqvi S, Razumilava N, Ribback S, et al. Cholangiocarcinomas can originate from hepatocytes in mice. J Clin Invest. 2012;122:2911–2915.

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