Progression of rat embryo fibroblast cells immortalized with transforming genes of human papillomavirus type 16.

To clarify the mechanism of cell transformation by human papillomavirus type 16 (HPV16), we constructed recombinant murine retroviruses containing various subgenomic fragments of the HPV16 early region and examined their abilities to transform rat fibroblasts in primary culture. The E7 ORF, but not the E6 ORF, immortalized cells in primary culture, but the recombinant retrovirus containing both the E6 and E7 ORFs did not transform them. However, after long-term cultivation of cells immortalized by E6 and E7 ORFs, some cells became transformed. During this progression, the amounts of viral mRNA and E7 protein did not change and virus rescued from progressed cells could not transform cells in primary culture, suggesting that some changes in cellular genes, but not viral genes, cause malignant progression of immortalized cells. During this process, the expression of c-K-ras mRNA and its product increased but that of c-myc mRNA did not.