Persistent infection with hepatitis C virus (HCV) is associated with the development of liver cirrhosis and hepatocellular carcinoma, To examine the oncogenic potential of the HCV core gene product, primary rat embryo fibroblasts (REFs) were transfected with the core gene in the presence or absence of the R-ms oncogene, In contrast to a previous report (R. B. Ray, L. M. Lagging, K. Meyer, and R. Ray, J. Virol. 70:4438-4443, 1996), HCV core proteins from two different genotypes (type la and type Ib) were not found to transform REFs to tumorigenic phenotype in cooperation with the W-ras oncogene, although the core protein was successfully expressed 20 days after transfection, In addition, REFs transfected with E1A-but not core-expressing plasmid showed the phenotype of immortalized cells when selected with G518. The biological activity was confirmed by observing the transcription activation from two viral promoters, Rous sarcoma virus long terminal repeat and simian virus 40 promoter, which are known to be activated by the core protein from HCV-1 isolate. In contrast to the result with primary cells, the Rat-1 cell line, stably expressing HCV core protein, exhibited focus formation, anchorage-independent growth, and tumor formation in nude mice, HCV core protein was able to induce the transformation of Rat-1 cells with various efficiencies depending on the expression level of the core protein, These results indicate that HCV core protein has an oncogenic potential to transform the Rat-1 cell line but is not sufficient to either immortalize primary REFs by itself or transform primary cells in conjunction with the H-ras oncogene.
