Abstract
Growing evidence suggests a mechanistic link between steatohepatitis and hepatocellular carcinoma (HCC). However, the lack of representative animal models hampers efforts to understand pathophysiological mechanisms underlying steatohepatitis-related HCC. We found that liver-specific deletion of Ssu72 phosphatase in mice, leads to a high incidence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, but not HCC. However, loss of Ssu72 drastically increased the probability of HCC developing, as well as the population of hepatic progenitors, in various chemical and metabolic syndrome-induced HCC models. Importantly, hepatic Ssu72 loss resulted in the induction of mature hepatocyte-to-progenitor cell conversion, by dedifferentiation orchestrated by Ssu72-mediated hypo-phosphorylation of hepatocyte nuclear factor 4α (HNF4α), a master regulator of hepatocyte function. Our findings suggest that Ssu72-mediated HNF4α transcription contributes to the progression of steatohepatitis-associated HCC by regulating the dedifferentiation potential of hepatocytes. Thus, targeting the Ssu72-mediated HNF4α signaling that underlies the pathogenesis of steatohepatitis-associated HCC development could be a novel therapeutic intervention for steatohepatitis-associated HCC.
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All data included in this work are presented in the paper and Supplementary Figures and Tables. Additional data relevant to this paper may be provided by the corresponding authors upon request.
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Acknowledgements
We would like to thank Dr. Valentina Factor (National Cancer institute, Bethesda, MD) and Dr. Shunsuke Matsuo (Gunma University, Japan) for kindly providing A6 antibody and Tfr2 promoter constructs, respectively.
Funding
This work was supported by grants [2017R1A2B3006776 (CWL) and 2018R1D1A1A02085616 (HSK)] of National Research Foundation (NSF) funded by the Ministry of Education, Science, and Technology (MEST), Republic of Korea.
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HSK and JSY designed the studies, performed and analyzed data, and wrote the parts of paper; YJ and HL generated conditional KO mice and analyzed data; EJP, JKL, SC, JYP, and HG contributed to specific experiments; CWL designed the studies, supervised the overall project, wrote the paper, and performed the final paper preparation. All authors provided feedback and agreed on the final paper.
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All animal experiments were conducted in accordance with guidelines of the IACUC 2018-05-16-2, IACUC 2019-04-31-1, IACUC 2020-08-33-1 and IACUC 2021-02-41-1 of Sungkyunkwan University, an institution accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International. Research with human liver specimens was approved by the Asan Medical Center Institutional Review Board (2019-0636).
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Kim, HS., Yoon, JS., Jeon, Y. et al. Ssu72-HNF4α signaling axis classify the transition from steatohepatitis to hepatocellular carcinoma. Cell Death Differ 29, 600–613 (2022). https://doi.org/10.1038/s41418-021-00877-x
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DOI: https://doi.org/10.1038/s41418-021-00877-x
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