Transforming activity of cells transfected with hepatitis C virus nonstructural protein NS3

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The association of hepatocellular carcinoma (HCC) with hepatitis C virus (HCV) infection has been suggested. However, its mechanism is unknown. Because the organization of HCV resembles that of members of the family Flaviviridae, a biological function of the HCV nonstructural protein NS3 may play a role. To test this, either human- or mouse-associated cells were transfected with an expression vector containing cDNA for the 5'-or 3'-half sequence of the HCV genome segment encoding NS3 (pRcHCNS3-5' and pRcHCNS3-3', respectively).1. When Hep G2 cells or IMR32 cells were transfected with the vectors, HCV-specific DNA was detected only in the cells transfected with pRcHCNS3-5'.2. NIH 3T3 cells were transfected and cell growth were determined. Only cells transfected with pRcHCNS3-5' rapidly proliferated and indeed, showed the colony formations.3. NIH 3T3 cells transfected with pRcHCNS3-5' were inoculated subcutaneously in the flank of nude mice. After 2 weeks of the inoculation, subcutaneous tumors were found 2 of 10 inoculated mice. In particular, all mice developed the tumor, which was defined microscopically as fibrosarcoma.4. The HCV-specific DNA fragment was able to be amplified in cells isolated from the tumors.These results suggest that 5' region of HCV-NS3 is involved in cell transformation. Further studies are needed to see whether this tumorigenic capability associated with the 5' region of HCV-NS3 plays a significant role for the carcinogenesis of the HCV-infected liver.