Regulation of Transforming Growth Factor a Gene Expression in an Ovarian Surface Epithelial Cell Line Derived from a Human Carcinoma1

Abstract

The surface epithelium plays an important role in normal ovarian physiology: the cells proliferate in the vicinity of the developing preovulatory 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) has been identified as a growth-promoting factor for normal surface epithelial cells from human ovaries and ovarian surface epithelial cell lines, we have examined the regulation of the TGF alpha gene in HEY cells, a surface epithelial cell line derived from a human ovarian carcinoma. Treatment of HEY cells for 60 h with estradiol-17 beta, dihydrotestosterone, 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 for TGF alpha. Treatment of HEY cells with TGF alpha increased the steady-state levels of TGF alpha mRNA, indicating that an autoregulatory mechanism could result in overexpression of TGF alpha. TGF beta, a known 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 derived, were found by quantitative polymerase chain reaction (PCR) to contain TGF beta 1 mRNA. The TGF beta 1 mRNA was translated into immunoreactive TGF beta 1, indicating that TGF beta can act in an autocrine manner. By use of quantitative PCR, HEY cells were shown to express the genes for the TGF beta receptor II, betaglycan and endoglin. By cross-linking, these components of the TGF beta receptor system were found 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 suggest that the levels of TGF alpha and the cell growth of normal and transformed surface epithelial cells from human ovaries may be regulated by the interaction of autoregulatory mechanisms involving TGF alpha and TGF beta ligand-receptor systems.