Infection of WHV/c-myc transgenic mice with Moloney murine leukaemia virus and proviral insertion near the syndecan-4 gene in an early liver tumour.
The capacity of Moloney murine leukaemia virus (MoMLV) to infect neonatal hepatocytes and to accelerate liver carcinogenesis was examined in a transgenic mouse model. WHV/c-myc mice which are highly susceptible to the development of liver tumours were infected with MoMLV shortly after birth, when expression of the murine ecotropic retroviral receptor gene was still detectable in the neonatal liver. All MoMLV-infected transgenic mice and non-transgenic littermates succumbed to T-cell lymphomas within 2-9 months; during this period of time, three infected transgenic animals developed primary hepatocellular carcinomas. Remarkably, one of these liver tumours arose significantly faster than tumours from uninfected WHV/c-myc controls, and it harboured a unique MoMLV provirus. The provirus integration site was located 5.5 kb upstream of the first exon of the syndecan-4 gene, which encodes a heparan sulphate proteoglycan implicated in growth factor activation and protein kinase C distribution in focal adhesions. Our data provide evidence for clonal MoMLV provirus integration in a hepatocellular carcinoma, and indicate that parenchymal liver cells may be susceptible to MoMLV infection following neonatal inoculation.
Unité de Recombinaison et Expression génétique (INSERM U.163), Institut Pasteur, Paris.
C A
CA
Renard
C
C
Transy
P
P
Tiollais
M A
MA
Buendia
D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000821:virology*; D018076:DNA, Complementary; D017919:Hepatitis B Virus, Woodchuck / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000821:virology; D008113:Liver Neoplasms / Q000378:metabolism / Q000821:virology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D008979:Moloney murine leukemia virus / Q000235:genetics / Q000502:physiology*; D011509:Proteoglycans / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D011533:Proviruses / Q000235:genetics / Q000502:physiology*; D051381:Rats; D011991:Receptors, Virus / Q000096:biosynthesis; D015183:Restriction Mapping; D012192:Retroviridae Infections / Q000150:complications / Q000821:virology; D053671:Syndecan-4; D014412:Tumor Virus Infections / Q000150:complications / Q000821:virology; D016662:Virus Integration
D018076:DNA, Complementary; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D016271:Proto-Oncogene Proteins c-myc; D011991:Receptors, Virus; C508306:Sdc4 protein, mouse; C508307:Sdc4 protein, rat; D053671:Syndecan-4; C070506:ecotropic murine leukemia virus receptor