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Cited by 46Hepatitis B Virus StudiesLiver physiology and pathologyCancer-related Molecular Pathways

Hepatitis B virus X protein promotes DNA damage propagation through disruption of liver polyploidization and enhances hepatocellular carcinoma initiation

Ahodantin, James, Bou-Nader, Myriam, Cordier, Corinne, Mégret, Jérôme, Soussan, Patrick, Desdouets, Chantal, Kremsdorf, Dina·2019·Oncogene
DOI 10.1038/s41388-018-0607-3
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Abstract

Hepatitis B virus X protein (HBx) contributes to Hepatitis B virus (HBV)-related liver cancer. However, its impact on hepatocyte proliferation and genomic stability remains elusive. We studied the role of HBx expression on the progression of cell cycle and liver polyploidization during proliferation and liver carcinogenesis. Full-length HBx transgenic mice (FL-HBx) were developed to investigate liver ploidy as well as hepatocyte proliferation, along normal liver maturation and during cancer initiation (chemical carcinogen treatment). Investigation of postnatal liver development in FL-HBx showed an aberrant G1/S and G2/M transitions, triggered (1) a delay of the formation of hepatocytes binucleation, (2) the early synthesis of polyploidy nuclei (≥4n) and (3) DNA damage appearance. Moreover, HBV infection during hepatocytes proliferation in a humanized liver mouse model led, to modifications in polyploidy of hepatocytes. In initiation of hepatocellular carcinoma, FL-HBx protein decreased ChK1 phosphorylation, Mre11 and Rad51 expression, upregulated IL-6 expression and impaired apoptosis. This was related to DNA damage accumulation in FL-HBx mice. At day 75 after initiation of hepatocellular carcinoma, FL-HBx mice revealed significant cell cycle changes related to the increased amount of 4n nuclei and of markers of cancer progenitor cells. Finally, PLK1 upregulation and p38/ERK activation in FL-HBx mice were implicated in aberrant polyploidization favoring DNA damage propagation…

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  • Telomere deprotection and infection by HBV or HCV promote polyploidisation via unknown mechanisms.

    “Telomere deprotection162 and infection by HBV or HCV163,164 were also reported to promote polyploidisation via unknown mechanisms.”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [164]

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Authors
Ahodantin, J., Bou-Nader, M., Cordier, C., Mégret, J., Soussan, P., Desdouets, C., & Kremsdorf, D.
Affiliations
Centre National de la Recherche Scientifique (FR)
Corresponding author
Kremsdorf, Dina
ORCID
Venue
Oncogene
Publisher
Springer Science and Business Media LLC
Published
2018-12-11
Volume
38
Issue
14
Pages
2645-2657
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
DOI
10.1038/s41388-018-0607-3
OpenAlex
W2904395019
Cited by
46
References
2
Citations by year
2026: 7 · 2025: 3 · 2024: 3 · 2023: 6 · 2022: 7 · 2021: 8 · 2020: 6 · 2019: 5 · 2017: 1
FWCI
3.71
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Oncogene (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
  • Institut National de la Santé et de la Recherche Médicale
  • Centre National de la Recherche Scientifique
Topics
  • Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
hepatitis B virus X protein, hepatocyte proliferation, cell cycle dysregulation, Chk1 phosphorylation, MRE11, RAD51, interleukin-6, apoptosis, cancer progenitor cells, PLK1, hepatocyte transformation, hepatocarcinogenesis
MeSH terms
Animals, Cell Cycle, DNA Damage, Hepatitis B virus, Carcinoma, Hepatocellular, Humans, Liver, Liver Neoplasms, Mice, Transgenic, Signal Transduction, Trans-Activators, Up-Regulation, Mice, SCID, Apoptosis, Hepatitis B, Chronic, Hepatocytes, Cell Proliferation, Mice, Viral Regulatory and Accessory Proteins, Carcinogenesis

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