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Immortalization by Human Papillomavirus Type 16 Alters Retinoid Regulation of Human Ectocervical Epithelial Cell Differentiation¹

Departments of Physiology and Biophysics [C. A., E. A. R., J. C. I., R. L. E.], Reproductive Biology [E. A. R., J. C. I., R. L. E.], Biochemistry [R. L. E.], Environmental Health Sciences [E. A. R.], and Dermatology [R. L. E.], Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

Human cervical cells are a primary site of papillomavirus infection and 90% of all cervical tumors are positive for human papillomavirus (HPV) DNA. Over one-half million cases of HPV-associated cervical, vulvar, and penile cancers are reported per year. Yet, in spite of the magnitude of this problem, the effects of HPV infection on cervical cell growth and differentiation are not well characterized. To study these effects we have developed a clonal cell line of HPV-16-immortalized ectocervical epithelial cells, ECE16-1.

In the present study we demonstrate that under normal growth conditions the cytokeratin content of ECE16-1 cells is dramatically altered compared to normal cervical cells; the level of K5, K6, K14, K16, and K17 is reduced and the level of K7, K8, and K19 is increased. We demonstrate that this change is largely due to a difference in the response of the cells to retinoids, as growth in retinoid-free medium produces a complete normalization of cytokeratin levels. Upon addition of natural and synthetic retinoids, the levels of cytokeratins K5, K6, K14, K16, and K17 are reduced, while the levels of cytokeratins K19, K7, and K8 are increased. Cytokeratin K13 levels are only slightly altered.

The level of involucrin, a precursor of the cervical cell envelope (superficial cell), is not changed by immortalization nor is it regulated by retinoids. Transglutaminase activity is also not appreciably altered by immortalization; however, ECE16-1 cells make fewer envelopes than normal ECE cells.

Our results clearly indicate that natural and synthetic retinoids suppress the differentiation of HPV transformed cervical cells. In early, low grade, cervical intraepithelial neoplasia, transcription of the HPV16 E6/E7 oncogenes is confined to the suprabasal layers. Our results suggest that retinoids, because they inhibit the differentiation of HPV16 immortalized cervical cells, may reduce the extent of viral oncogene transcription and thus be useful in slowing the neoplastic process.

¹ This work utilized the facilities of the Skin Diseases Research Center of Northeast Ohio (NIH AR39750) and was supported by a grant from the American Institute for Cancer Research (R. L. E.).

Received 2/ 4/91. Accepted 5/17/91.

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