HIGH-LEVEL EXPRESSION OF THE RETINOIC ACID RECEPTOR-BETA GENE IN NORMAL-CELLS OF THE UTERINE CERVIX IS REGULATED BY THE RETINOIC ACID RECEPTOR-ALPHA AND IS ABNORMALLY DOWN-REGULATED IN CERVICAL-CARCINOMA CELLS

Retinoic acid (RA) is essential for regulation of epithelial cell diff erentiation, The intracellular effects of RA are mediated hy RA-bindin g nuclear receptors, including the RA receptors (RARs) alpha, beta, an d gamma. The ligand-activated receptors induce the transcription of ta rget genes by binding to RA-responsive elements in the promoter region s, One target gene is the RAR beta gene, which encodes a potential tum or suppressor. Loss of RA inducibility of RAR beta gene expression is assumed to play a role in the development of several types of human ca rcinomas, including carcinomas of the uterine cervix. We have analyzed RAR beta gene expression in normal cervical cells and in cervical car cinoma cell lines, The result how that the RAR beta mRNA levels are hi gh and RA inducible in the primary keratinocytes, whereas they are low and not inducible or only slightly inducible by RA in all of the cerv ical carcinoma cell lines analyzed. The basal and the RA-induced RAR b eta mRNA levels tend to increase with senescence of the normal cells, Fusion of primary ectocervical keratinocytes with HeLa cervical carcin oma cells revealed that the characteristics of RAR beta gene expressio n of the normal cells are dominant over that of the tumor cells, Using synthetic retinoids with receptor-preferential agonist activities and a RAR alpha-specific antagonist, we show that RAR alpha is the major endogenous RAR subtype For induction of RA-dependent RAR beta gene exp ression. Taken together, our results indicate that abnormal down-regul ation of RAR beta gene expression may be an important step in the mult ifactorial process of cervical carcinogenesis.