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Protéine HBx du virus de l'hépatite B : impacts sur la polyploïdisation hépatique au cours du développement et de la maladie du foie

Abstract : Hepatitis B virus X protein (HBx) is involved in the development of hepatocellular carcinoma (HCC). However, how HBx promotes genetic instability or DNA damage during liver proliferation remains unclear. For that, we used mice transgenic for the full-length HBx (FL-HBx) to investigated the impact of HBx expression on polyploidization during normal liver proliferation and in liver diseases (fibrosis : carbon tetrachloride and HCC : diethyl nitrosamine, treatments). During postnatal liver development as well as in liver diseases, FL-HBx inhibits liver binucleation and triggers early production of polyploid nuclei (≥ 4n). These features were associated with aberrant G1/S and G2/M transitions and the propagation of DNA damage. Furthermore, hepatitis B virus infection, in liver humanized mouse model, shows similar deregulation of hepatocytes polyploidization. In FL-HBx animals, HCC initiation was associated with impairment of ChK1 activation and Mre11 and Rad51 expression (DNA repair proteins), inhibited apoptosis and upregulated IL-6 transcription while in fibrosis, increased expression of α-sma, PdgfR-β, TGF-β, TNF-α as well as a defect in glutamine synthetase expression were observed. In addition, treated FL-HBx animals displayed marked alterations to the cell cycle associated with stronger expression of HCC progenitor cell markers (Ly6D, GpC3, AFP). Finally, we showed that FL-HBx protein induces pathological polyploidization of hepatocytes by upregulating PLK1 through p38/ERK Mapks pathways. That promotes a loss of genomic integrity and an increase of hepatocytes expressing tumor progenitor cell markers during liver fibrosis and HCC initiation.
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https://tel.archives-ouvertes.fr/tel-01811690
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Submitted on : Sunday, June 10, 2018 - 1:02:30 AM
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  • HAL Id : tel-01811690, version 1

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James Ahodantin. Protéine HBx du virus de l'hépatite B : impacts sur la polyploïdisation hépatique au cours du développement et de la maladie du foie. Virologie. Université Pierre et Marie Curie - Paris VI, 2017. Français. ⟨NNT : 2017PA066373⟩. ⟨tel-01811690⟩

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