REGULATION OF TRANSFORMING GROWTH-FACTOR AC GENE-EXPRESSION IN AN OVARIAN SURFACE EPITHELIAL-CELL LINE DERIVED FROM A HUMAN CARCINOMA

The surface epithelium plays an important role in normal ovarian physi ology: the cells proliferate in the vicinity of the developing preovul atory follicle to accommodate the increase in follicular size, and to repair the surface after ovulation. These bouts of mitotic activity in vivo must be strictly regulated by the activity of growth factors and their receptors. Since transforming growth factor alpha (TGF alpha) h as been identified as a growth-promoting factor for normal surface epi thelial cells from human ovaries and ovarian surface epithelial cell l ines, we have examined the regulation of the TGF alpha gene in HEY cel ls, a surface epithelial cell line derived from a human ovarian carcin oma. Treatment of HEY cells for 60 h with estradiol-17 beta, dihydrote stosterone, or progesterone at concentrations ranging from 5 x 10(-8) to 5 x 10(-6) M did not influence the level of the 4.5-kb transcript f or TGF alpha. Treatment of HEY cells with TGF alpha increased the stea dy-state levels of TGF alpha mRNA, indicating that an autoregulatory m echanism could result in overexpression of TGF alpha. TGF beta, a know n growth inhibitor of ovarian surface epithelial cells, decreased the steady-state levels of TGF alpha mRNA, suggesting a mechanism by which the levels of TGF alpha and mitotic activity could be regulated. HEY cells, like the human surface epithelial cells from which they were de rived, were found by quantitative polymerase chain reaction (PCR) to c ontain TGF beta, mRNA. The TGF beta(1), mRNA was translated into immun oreactive TGF beta(1), indicating that TGF beta can act in an autocrin e manner. By use of quantitative PCR, HEY cells were shown to express the genes for the TGF beta receptor II, betaglycan and endoglin. By cr oss-linking, these components of the TGF beta receptor system were fou nd to bind TGF beta(1). This is the first demonstration of expression of functional TGF beta receptors in HEY cells and represents the first demonstration in an ovarian cell system. In summary, our findings sug gest that the levels of TGF alpha and the cell growth of normal and tr ansformed surface epithelial cells from human ovaries may be regulated by the interaction of autoregulatory mechanisms involving TGF alpha a nd TGF beta ligand-receptor systems.