Retinoid regulation of cell differentiation in a series of human papillomavirus type 16-immortalized human cervical epithelial cell lines.

Retinoids are important regulators of cervical epithelial cell differentiation and have been used in the treatment of cervical cancer. In the present study we evaluate the effects of retinoic acid on expression of biochemical markers of differentiation and expression of human papillomavirus reading frames encoding the early gene products E6 and E7 in normal and HPV16-immortalized cervical epithelial cell lines. Our results indicate that the differentiation markers cytokeratins K5 and K16 and transglutaminase type 1 are suppressed by all-trans-retinoic acid (RA). A marked concentration-dependent reduction in the level of of each mRNA is observed with maximal suppression at 1 microM. Each of the HPV16-immortalized cell lines (ECE16-1, ECE16-D1 and ECE16-D2) are more sensitive to the effects of RA than normal cells. The level of HPV16 transcript encoding E6/E7 is not significantly suppressed by 1 microM RA in ECE16-1 cells, but is suppressed in ECE16-D1 and ECE16-D2 cells. In addition, an increase in HPV transcripts encoding E6/E7 is observed at intermediate (10 and 100 nM) retinoic acid concentrations in ECE16-1 and ECE16-D2 cells, but not in ECE16-D1 cells. Our results show that retinoids regulate E6/E7 transcript levels in some cervical cell lines but not in others, suggesting that different cervical tumors may respond to retinoids via different mechanisms.