LACK OF SELF-REGULATION OF HUMAN CHORIONIC-GONADOTROPIN BIOSYNTHESIS IN HUMAN CHORIOCARCINOMA CELLS

Human gestational trophoblastic neoplasms overexpress hCG/LH receptors . Whether this overexpression is a reflection of a loss of self-regula tion of hCG biosynthesis was investigated using JAR human choriocarcin oma cells. The results show that exogenous hCG did not affect steady s tate hCG alpha and hCG beta mRNA or dimer hCG protein levels in JAR ce lls. The JAR cells, however, responded to 8-bromo-cAMP with an increas e in hCG alpha mRNA levels, suggesting that cAMP-mediated regulation o f the hCG subunit genes was intact in the cells. Disruption of recepto r function by a receptor antibody, which resulted in an increase in hC G alpha mRNA levels and hCG secretion in normal trophoblasts, had no e ffect on JAR cells. Unlike normal trophoblasts, which contain a predom inant receptor transcript of 1.8 kilobases (kb), with minor higher mol ecular size (7.5 and 5.4 kb) transcripts occasionally seen, JAR cells contain a higher abundance of multiple transcripts (7.5, 5.4, 3.5, and 1.8 kb), with the predominant transcript being 5.4 kb. In addition, a lthough normal trophoblasts contain an 80-kilodalton receptor protein, JAR cells contain only a 50-kilodalton hCG/LH receptor isoform. In co ntrast to the effects of exogenous hCG on normal placental tissue in v itro, it was unable to down-regulate receptor transcripts or receptor protein in JAR cells. In summary, JAR cells lack the ability to self-r egulate hCG biosynthesis. This loss could explain how hCG can reach ve ry high levels in gestational trophoblastic disease compared to those in normal pregnancy.