title: C-terminal-truncated hepatitis B virus X protein enhances the development of diethylnitrosamine-induced hepatocellular carcinogenesis.
abstract: Hepatitis B virus X protein (HBx) is involved in the development of hepatocellular carcinoma (HCC). The HBx sequence is a preferential site of integration into the human genome, leading to the formation of C-terminal-truncated HBx proteins (Ct-HBx). We previously reported that Ct-HBx proteins were able to potentiate cell transformation in vitro. Our present goal was to compare the ability of Ct-HBx and full-length HBx (FL-HBx) proteins to develop or enhance HCC in transgenic mice. In the absence of treatment, neither Ct-HBx- nor FL-HBx-transgenic mice developed HCC. In young mice treated with diethylnitrosamine (DEN) at 8 months of age, a significantly higher incidence and number of liver lesions were observed in Ct-HBx mice than in FL-HBx and control mice. The earlier development of tumours in Ct-HBx-transgenic mice was associated with increased liver inflammation. At 10 months, macroscopic and microscopic analyses showed that, statistically, FL-HBx mice developed more liver lesions with a larger surface area than control mice. Furthermore, during DEN-induced initiation of HCC, Ct-HBx- and FL-HBx-transgenic mice showed higher expression of IL-6, TNF-α and IL-1β transcripts, activation of STAT3, ERK and JNK proteins and an increase in cell apoptosis. In conclusion, in DEN-treated transgenic mice, the expression of Ct-HBx protein causes a more rapid onset of HCC than does FL-HBx protein. HBV genome integration leading to the expression of a truncated form of HBx protein may therefore facilitate HCC development in chronically infected patients.
authors.affiliation: Institut Pasteur, Département de Virologie, Paris, France.|Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine Necker, Paris, France.|Inserm, U845, Team 'Pathogenèse des hépatites virales B et immunothérapie', Paris, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Quetier
authors.affiliation: Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine Necker, Paris, France.|Inserm, U845, Team 'Pathogenèse des hépatites virales B et immunothérapie', Paris, France.|Institut Pasteur, Département de Virologie, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Brezillon
authors.affiliation: Institut Pasteur, Département de Virologie, Paris, France.|Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine Necker, Paris, France.|Inserm, U845, Team 'Pathogenèse des hépatites virales B et immunothérapie', Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Revaud
authors.affiliation: Institut Pasteur, Département de Virologie, Paris, France.|Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine Necker, Paris, France.|Inserm, U845, Team 'Pathogenèse des hépatites virales B et immunothérapie', Paris, France.
authors.forename: James
authors.initials: J
authors.lastname: Ahodantin
authors.affiliation: Institut Pasteur, Département de Virologie, Paris, France.|Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine Necker, Paris, France.|Inserm, U845, Team 'Pathogenèse des hépatites virales B et immunothérapie', Paris, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: DaSilva
authors.affiliation: Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine Necker, Paris, France.|Institut Pasteur, Département de Virologie, Paris, France.|Service de Virologie, Hôpital Tenon, Paris, France.|Université Pierre et Marie Curie, Paris, France.|Inserm, U845, Team 'Pathogenèse des hépatites virales B et immunothérapie', Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Soussan
authors.affiliation: Institut Pasteur, Département de Virologie, Paris, France.|Université Paris Descartes, Sorbonne Paris-Cité, Faculté de Médecine Necker, Paris, France.|Inserm, U845, Team 'Pathogenèse des hépatites virales B et immunothérapie', Paris, France.
authors.forename: Dina
authors.initials: D
authors.lastname: Kremsdorf
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000821:virology*; D049109:Cell Proliferation; D004052:Diethylnitrosamine / Q000633:toxicity; D015967:Gene Expression Regulation, Viral; D006515:Hepatitis B virus / Q000472:pathogenicity*; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology / Q000821:virology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000821:virology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D015534:Trans-Activators / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D004052:Diethylnitrosamine