INTEGRATED HEPATITIS-B VIRUS-X AND 3' TRUNCATED PRES S-SEQUENCES DERIVED FROM HUMAN HEPATOMAS ENCODE FUNCTIONALLY ACTIVE TRANSACTIVATORS/

The hepatitis B virus (HBV) frequently integrates into hepatocellular genomic DNA during viral infection. Transcriptional transactivators en coded by integrated HBV X and 3' truncated preS/S sequences are known to stimulate gene expression from homologous and heterologous promoter s. Here we demonstrate that 21 of 26 (81%) hepatocellular carcinoma ti ssues/cell lines contain coding sequences for at least one of the two known transactivators. Pour integrated X and three preS/S transactivat or sequences contained in five isolates from three hepatoma primary ti ssues or cell lines were used as examples to prove functionality of th e encoded transactivators, In one case, where both X and preS/S sequen ces were present, dissection of X and preS/S transactivator sequences showed independent functionality. The investigation of X- and preS/S-s pecific RNA and protein expression revealed the existence of. carboxyt erminally truncated viral-cellular fusion proteins that were able to s timulate gene expression from the c-fos proto-oncogene promoter five- to ten-fold. These results demonstrate that structurally intact HBV tr ansactivator sequences are integrated in the majority of HBV-associate d HCCs/hepatoma cell lines. In all tested examples integrated DNAs had retained functionality as transactivators. This data thereby support indirectly the hypothesis of a possible involvement of HBV transactiva tors in liver cell proliferation and hepatocarcinogenesis.