INTEGRATION OF HIGH-RISK HUMAN PAPILLOMAVIRUS DNA IS LINKED TO THE DOWN-REGULATION OF CLASS-I HUMAN-LEUKOCYTE ANTIGENS BY STEROID-HORMONES IN CERVICAL TUMOR-CELLS

A crucial event in the malignant progression of cervical intraepitheli al neoplasia appears to be the up-regulation of high-risk human papill omavirus (HPV) early gene expression, Steroid hormones have been linke d to the progression from premalignant to neoplastic status in HPV pos itive lesions, This report demonstrates that at physiological levels, the glucocorticoid hormone hydrocortisone consistently down-regulates class I human leukocyte antigen (HLA) surface expression in HPV-positi ve cervical tumor cells but can up-regulate expression in HPV-negative epithelial tumor lines, Suppression of HLA expression was also seen w ith progesterone, another steroid hormone, The hydrocortisone-mediated medulation of HLA expression is dependent on integration and transcri ption of the HPV genome and can be blocked by Ru38486, an antagonist o f both glucocorticoid and progesterone receptors, indicating the role of these receptors in mediating HLA suppression, The data suggest that HPV integration events in cervical epithelia correlate with hormone-d ependent HLA suppression, possibly contributing to the avoidance of tu mor recognition by cytotoxic T cells, These studies imply that clinica l use of steroids may be contraindicated in HPV-positive individuals w ho have early premalignant cervical disease or neoplasia but provide e vidence that the antiprogestin Ru38486 may be useful in the management of early stage cervical disease.