INFECTION OF WHV C-MYC TRANSGENIC MICE WITH MOLONEY MURINE LEUKEMIA-VIRUS AND PROVIRAL INSERTION NEAR THE SYNDECAN-4 GENE IN AN EARLY LIVER-TUMOR/

The capacity of Moloney murine leukaemia virus (MoMLV) to infect neona tal 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 recept or gene was still detectable in the neonatal liver. All MoMLV-infected transgenic mice and non-transgenic littermates succumbed to T-cell ly mphomas within 2-9 months; during this period of time, three infected transgenic animals developed primary hepatocellular carcinomas. Remark ably, one of these liver tumours arose significantly faster than tumou rs from uninfected WHV/c-myc controls, and it harboured a unique MoMLV provirus. The provirus integration site was located 5.5 kb upstream o f the first exon of the syndecan-4 gene, which encodes a heparan sulph ate proteoglycan implicated in growth factor activation and protein ki nase C distribution in focal adhesions. Our data provide evidence for clonal MoMLV provirus integration in a hepatocellular carcinoma, and i ndicate that parenchymal liver cells may be susceptible to MoMLV infec tion following neonatal inoculation.