The hepatitis B virus X gene potentiates c-myc-induced liver oncogenesis in transgenic mice.
The hepatitis B virus X protein (HBx) is thought to be implicated in the development of hepatocellular carcinoma, but its exact function remains controversial. Transgenic mice from PEX7 and AX16 lineages that express HBx in the liver under control of different viral regulatory elements develop no liver pathology (Billet et al., 1995). We have crossed these two mouse lineages with WHV/c-myc oncomice in which liver-specific expression of c-myc driven by woodchuck hepatitis virus (WHV) regulatory sequences causes liver cancer in all animals. The average tumor latency was shortened by 2 to 3 months in bitransgenic animals from all populations compared with simple c-myc transgenic littermates. At preneoplastic stages, adult bitransgenic mice showed four to fivefold enhanced expression of the c-myc transgene, increased hepatocyte proliferation and more extensive liver lesions compared with simple WHV/c-myc transgenics. Thus in this model, HBx alone has no direct pathological effect but it is shown to accelerate tumor development induced by c-myc. The data presented here firmly establish the oncogenic potential of HBx, apparently acting as a tumor promoter. This model offers unique opportunities to investigate the mechanisms by which HBx trans-activates the expression of target genes and deregulates the hepatocyte growth control in vivo.
Terradillos
O
O
Unité de Recombinaison et Expression Génétique (INSERM U163), Institut Pasteur, Paris, France.
Billet
O
O
Renard
C A
CA
Levy
R
R
Molina
T
T
Briand
P
P
Buendia
M A
MA
D000818:Animals; D000990:Antithrombin III / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D004279:DNA, Viral / Q000032:analysis; D016259:Genes, myc; D006511:Hepatitis B Antigens / Q000096:biosynthesis / Q000235:genetics; D017919:Hepatitis B Virus, Woodchuck / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000473:pathology / Q000821:virology; D008113:Liver Neoplasms / Q000473:pathology / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D016366:Open Reading Frames; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*; D012367:RNA, Viral / Q000032:analysis; D012045:Regulatory Sequences, Nucleic Acid; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D054334:Viral Regulatory and Accessory Proteins
D004279:DNA, Viral; D006511:Hepatitis B Antigens; D016271:Proto-Oncogene Proteins c-myc; D012367:RNA, Viral; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D000990:Antithrombin III