Growth-regulating functions of human papillomavirus early gene products in cervical cancer cells acting dominant over enhanced epidermal growth factor receptor expression.

Squamous cell carcinomas of the human anogenital tract are usually associated with infection of specific types of human papillomaviruses (HPV 16, 18, 31, 33, 35). The intracellular concentration of human papillomavirus early gene products E6 and E7 has been directly linked to the proliferative capacity of cervical cancer cells. Since the expression rate of epidermal growth factor receptor correlates to growth properties in squamous carcinoma cell lines, it has been presumed that human papillomavirus early genes influence cell growth via enhanced epidermal growth factor receptor expression. This hypothesis implies that growth regulation by epidermal growth factor receptor overexpression dominates over a growth-regulatory influence of human papillomavirus early gene products in squamous carcinoma cells. To test this hypothesis epidermal growth factor receptor expression was analyzed in various clones of the C4-1 cervical cancer cell line which, upon dexamethasone treatment, express either increased or decreased levels of human papillomavirus 18 early gene products. In C4-1 clones expressing reduced levels of viral E6/E7 gene products upon glucocorticoid treatment expression of epidermal growth factor receptor was the same as in those clones displaying increased levels of papillomavirus proteins under identical culture conditions. The growth rate of the cells correlated with the level of viral gene products rather than with the expression of epidermal growth factor receptor. These findings suggest that unregulated overexpression of epidermal growth factor receptor is not the dominant mechanism of growth control in papillomavirus-positive carcinoma cells. Other, yet unknown pathways associated with papillomavirus early genes are essentially involved in growth control mechanisms of human cervical cancer cells.