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Cited by 34Liver physiology and pathologyWnt/β-catenin signaling in development and cancerHepatocellular Carcinoma Treatment and Prognosis

Cell fate analysis of zone 3 hepatocytes in liver injury and tumorigenesis

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Kurosaki, Shigeyuki, Nakagawa, Hayato, Hayata, Yuki, Kawamura, Satoshi, Matsushita, Yuki, Yamada, Tomoharu, Uchino, Koji, Hayakawa, Yoku +9 more·2021·JHEP Reports
DOI 10.1016/j.jhepr.2021.100315PMC PMC8319533
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Abstract

BACKGROUND & AIMS: Liver lobules are typically subdivided into 3 metabolic zones: zones 1, 2, and 3. However, the contribution of zonal differences in hepatocytes to liver regeneration, as well as to carcinogenic susceptibility, remains unclear. METHODS: We developed a new method for sustained genetic labelling of zone 3 hepatocytes and performed fate tracing to monitor these cells in multiple mouse liver tumour models. RESULTS: cell distribution closely matched that of the zone 3 marker CYP2E1. Cell fate analysis revealed that zone 3 hepatocytes maintained their own lineage but rarely proliferated beyond their liver zonation during homoeostasis; this indicated that our protocol enabled persistent genetic labelling of zone 3 hepatocytes. Using this system, we found that zone 3 hepatocytes generally had high neoplastic potential, which was promoted by constitutive activation of Wnt/β-catenin signalling in the pericentral area. However, the frequency of zone 3 hepatocyte-derived tumours varied depending on the regeneration pattern of the liver parenchyma in response to liver injury. Notably, Axin2-expressing hepatocytes undergoing chronic liver injury significantly contributed to liver regeneration and possessed high neoplastic potential. Additionally, we revealed that the metabolic phenotypes of liver tumours were acquired during tumorigenesis, irrespective of their spatial origin. CONCLUSIONS: Hepatocytes receiving Wnt/β-catenin signalling from their microenvironment have high neoplastic potential, and Wnt/β-catenin signalling is a potential drug target for the prevention of hepatocellular carcinoma. LAY SUMMARY: Lineage tracing revealed that zone 3 hepatocytes residing in the pericentral niche have high neoplastic potential. Under chronic liver injury, hepatocytes receiving Wnt/β-catenin signalling broadly exist across all hepatic zones and significantly contribute to liver tumorigenesis as well as liver regeneration. Wnt/β-catenin signalling is a potential drug target for the prevention of hepatocellular carcinoma.

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  • Previous studies have shown that cells in zone 3 can transform into HCC.

    “Previous studies have shown that cells in zone 3 can transform into HCC (22–24), but there has not been a head-to-head comparison to assess cancer formation from different zones.”

    From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [23]

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Authors
Kurosaki, S., Nakagawa, H., Hayata, Y., Kawamura, S., Matsushita, Y., Yamada, T., Uchino, K., Hayakawa, Y., Suzuki, N., Hata, M., Tsuboi, M., Kinoshita, H., Tanaka, Y., Nakatsuka, T., Hirata, Y., Tateishi, K., & Koike, K.
Affiliations
  • The University of Tokyo (JP)
  • The Institute of Medical Science, Asahi Life Foundation (JP)
  • Institute of Medical Science, The University of Tokyo (JP)
Corresponding author
Nakagawa, Hayato
ORCID
Venue
JHEP Reports
Publisher
Elsevier BV
Published
2021-08
Volume
3
Issue
4
Pages
100315
ISSN
2589-5559 (ISSN-L)
DOI
10.1016/j.jhepr.2021.100315
PMC
PMC8319533
OpenAlex
W3171779636
Cited by
34
References
8
Citations by year
2026: 5 · 2025: 9 · 2024: 8 · 2023: 7 · 2022: 4 · 2021: 1
FWCI
2.78
Type
journal article
Language
en
Open access
Licence
Locations
  • JHEP Reports (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • AMED
  • Life Science Foundation of Japan
  • Cell Science Research Foundation
  • The Naito Science and Engineering Foundation
  • Takeda Science Foundation
  • MSD Life Science Foundation
  • Bristol-Myers Squibb Co
  • Mitsubishi Foundation
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
Keywords
liver zonation, Wnt/β-catenin signaling, Axin2, chronic liver injury, liver regeneration, hepatocellular carcinoma, CYP2E1, hepatocarcinogenesis

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