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 encoded by integrated HBV X and 3' truncated preS/S sequences are known to stimulate gene expression from homologous and heterologous promoters. Here we demonstrate that 21 of 26 (81%) hepatocellular carcinoma tissues/cell lines contain coding sequences for at least one of the two known transactivators. Four integrated X and three preS/S transactivator sequences contained in five isolates from three hepatoma primary tissues or cell lines were used as examples to prove functionality of the encoded transactivators. In one case, where both X and preS/S sequences were present, dissection of X and preS/S transactivator sequences showed independent functionality. The investigation of X- and preS/S-specific RNA and protein expression revealed the existence of carboxyterminally truncated viral-cellular fusion proteins that were able to stimulate gene expression from the c-fos proto-oncogene promoter five- to ten-fold. These results demonstrate that structurally intact HBV transactivator sequences are integrated in the majority of HBV-associated 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 transactivators in liver cell proliferation and hepatocarcinogenesis.
Schlüter
V
V
Max-Planck-Institut für Biochemie, Department of Virus Research, Martinsried, Germany.
Meyer
M
M
Hofschneider
P H
PH
Koshy
R
R
Caselmann
W H
WH
D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000821:virology; D002999:Clone Cells; D017931:DNA Primers; D006367:HeLa Cells; D006514:Hepatitis B Surface Antigens / Q000235:genetics*; D006515:Hepatitis B virus / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000821:virology; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011498:Protein Precursors / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D012334:RNA, Neoplasm; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D054334:Viral Regulatory and Accessory Proteins; D016662:Virus Integration
D017931:DNA Primers; D006514:Hepatitis B Surface Antigens; C000715470:MAS1 protein, human; D011498:Protein Precursors; D000090063:Proto-Oncogene Mas; D012334:RNA, Neoplasm; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; C050806:presurface protein 1, hepatitis B surface antigen