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 t he development of hepatocellular carcinoma, but its exact function rem ains controversial, Transgenic mice from PEX7 and AX16 lineages that e xpress HBx in the liver under control of different viral regulatory el ements develop no liver pathology (Billet ed al., 1995), We have cross ed these two mouse lineages with WHV/c-myc oncomice in which liver-spe cific expression of c-myc driven by woodchuck hepatitis virus (WHV) re gulatory sequences causes liver cancer in all animals, The average tum or 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 prol iferation and more extensive liver lesions compared with simple WHV/c- myc transgenics, Thus in this model, HBx alone has no direct pathologi cal effect but it is shown to accelerate tumor development induced by c-myc. The data presented here firmly establish the oncogenic potentia l of HBx, apparently acting as a tumor promoter, This model offers uni que opportunities to investigate the mechanisms by which HBx trans-act ivates the expression of target genes and deregulates the hepatocyte g rowth control in vivo.