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High-Level Expression of the Retinoic Acid Receptor ß Gene in Normal Cells of the Uterine Cervix Is Regulated by the Retinoic Acid Receptor and Is Abnormally Down-Regulated in Cervical Carcinoma Cells¹

German Cancer Research Center, D-69120 Heidelberg, Germany [C. G., C. D., C. B., A. K., E. S.]; Department of Obstetrics and Gynecology, Ruprecht-Karls-University, D-69115 Heidelberg, Germany [B. G.]; and F. Hoffmann-LaRoche AG, CH-4070 Basel, Switzerland [W. B.]

Retinoic acid (RA) is essential for regulation of epithelial cell differentiation. The intracellular effects of RA are mediated by RA-binding nuclear receptors, including the RA receptors (RARs) , ß, and . The ligand-activated receptors induce the transcription of target genes by binding to RA-responsive elements in the promoter regions. One target gene is the RARß gene, which encodes a potential tumor suppressor. Loss of RA inducibility of RARß gene expression is assumed to play a role in the development of several types of human carcinomas, including carcinomas of the uterine cervix. We have analyzed RARß gene expression in normal cervical cells and in cervical carcinoma cell lines. The results show that the RARß mRNA levels are high and RA inducible in the primary keratinocytes, whereas they are low and not inducible or only slightly inducible by RA in all of the cervical carcinoma cell lines analyzed. The basal and the RA-induced RARß mRNA levels tend to increase with senescence of the normal cells. Fusion of primary ectocervical keratinocytes with HeLa cervical carcinoma cells revealed that the characteristics of RARß gene expression of the normal cells are dominant over that of the tumor cells. Using synthetic retinoids with receptor-preferential agonist activities and a RAR-specific antagonist, we show that RAR is the major endogenous RAR subtype for induction of RA-dependent RARß gene expression. Taken together, our results indicate that abnormal down-regulation of RARß gene expression may be an important step in the multifactorial process of cervical carcinogenesis.

¹ This work was supported in part by a grant from F. Hoffmann-La Roche, Ltd.

² To whom requests for reprints should be addressed, at German Cancer Research Center (Deutsches Krebsforschungszentrum), Applied Tumor Virology 0640, Im Neuenheimer Feld 242, D-69120 Heidelberg, Germany. Phone: 49 6221 424853; Fax: 49 6221 424852; E-mail: e.schwarz@dkfz-heidelberg.de.

Received 10/15/96. Accepted 2/17/97.

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