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-regulation of hCG biosynthesis was investigated using JAR human choriocarcinoma cells. The results show that exogenous hCG did not affect steady state hCG alpha and hCG beta mRNA or dimer hCG protein levels in JAR cells. The JAR cells, however, responded to 8-bromo-cAMP with an increase in hCG alpha mRNA levels, suggesting that cAMP-mediated regulation of the hCG subunit genes was intact in the cells. Disruption of receptor function by a receptor antibody, which resulted in an increase in hCG alpha mRNA levels and hCG secretion in normal trophoblasts, had no effect on JAR cells. Unlike normal trophoblasts, which contain a predominant receptor transcript of 1.8 kilobases (kb), with minor higher molecular 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, although normal trophoblasts contain an 80-kilodalton receptor protein, JAR cells contain only a 50-kilodalton hCG/LH receptor isoform. In contrast to the effects of exogenous hCG on normal placental tissue in vitro, it was unable to down-regulate receptor transcripts or receptor protein in JAR cells. In summary, JAR cells lack the ability to self-regulate hCG biosynthesis. This loss could explain how hCG can reach very high levels in gestational trophoblastic disease compared to those in normal pregnancy.
Licht
P
P
Department of Obstetrics and Gynecology, University of Louisville School of Medicine, Kentucky 40292.
Cao
H
H
Zuo
J
J
Lei
Z M
ZM
Rao
V
V
Merz
W E
WE
Day
T G
TG
D002822:Choriocarcinoma / Q000378:metabolism*; D006063:Chorionic Gonadotropin / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D011974:Receptors, LH / Q000235:genetics; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000378:metabolism*
D006063:Chorionic Gonadotropin; D012333:RNA, Messenger; D011974:Receptors, LH