HEPATITIS-C VIRUS CORE FROM 2 DIFFERENT GENOTYPES HAS AN ONCOGENIC POTENTIAL BUT IS NOT SUFFICIENT FOR TRANSFORMING PRIMARY RAT EMBRYO FIBROBLASTS IN COOPERATION WITH THE H-RAS ONCOGENE

Persistent infection with hepatitis C virus (HCV) is associated with t he development of liver cirrhosis and hepatocellular carcinoma, To exa mine 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 re port (R. B. Ray, L. M. Lagging, K. Meyer, and R. Ray, J. Virol. 70:443 8-4443, 1996), HCV core proteins from two different genotypes (type la and type Ib) were not found to transform REFs to tumorigenic phenotyp e in cooperation with the W-ras oncogene, although the core protein wa s successfully expressed 20 days after transfection, In addition, REFs transfected with E1A-but not core-expressing plasmid showed the pheno type of immortalized cells when selected with G518. The biological act ivity was confirmed by observing the transcription activation from two viral promoters, Rous sarcoma virus long terminal repeat and simian v irus 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 f ormation, anchorage-independent growth, and tumor formation in nude mi ce, HCV core protein was able to induce the transformation of Rat-1 ce lls with various efficiencies depending on the expression level of the core protein, These results indicate that HCV core protein has an onc ogenic potential to transform the Rat-1 cell line but is not sufficien t to either immortalize primary REFs by itself or transform primary ce lls in conjunction with the H-ras oncogene.