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Eppley Institute for Research in Cancer and Allied Diseases (A.K.M.-L., E.B., R.W.R.); Departments of Biochemistry and Molecular Biology (A.K.M.-L., R.W.R.), Obstetrics and Gynecology (J.R.), and Pharmacology (E.B., R.W.R.), University of Nebraska Medical Center, Omaha, Nebraska 68198; and Women’s Services Professional Corporation (C.J.L.), Omaha, Nebraska 68132
Address all correspondence and requests for reprints to: Dr. Raymond W. Ruddon, Corporate Office of Science and Technology, Johnson & Johnson, 410 George Street, New Brunswick, New Jersey 08901. E-mail: rruddon{at}corus.jnj.com
The hCGß gene family contains six genes linked in tandem on chromosome 19 and labeled ß genes 7, 8, 5, 1, 2, and 3. Previous studies on a small number of placentas have indicated that ß gene 5 was the most highly expressed gene during the first trimester of pregnancy, followed by genes 3 and 8. ß genes 7, 1, and 2 were expressed at very low levels. The purpose of this study was to determine 1) whether this pattern of expression was typical during normal pregnancy by sampling a large number of first trimester placentas, and 2) whether there was a correlation between gestational age and the pattern of hCGß gene expression. Total RNA from 27 first trimester placentas varying in age from 6–16 weeks was reverse transcribed into complementary DNA. The complementary DNA was amplified by PCR, and the amount of DNA representative of each hCGß gene was quantified by Genescan analysis. In 14 of the 27 placentas, hCGß gene 5 accounted for 50% or more of the total ß messenger RNA expressed. ß gene 3 was expressed at levels ranging from 1–42% of the total, and ß gene 8 expression ranged from 12–32% of the total. Gene 7 expression was less than 3% of the total ß expression in all 27 placentas. Although there appeared to be a trend toward lower expression of ß gene 3 in placentas beyond 10 weeks gestational age, there was no correlation of the pattern of ß expression with placental age. ß gene expression was also examined in two blighted ova, a spontaneous abortion sample, and a hydatidiform mole as well as in cultured JAR choriocarcinoma cells. With the exception of JAR cells, these abnormal tissues had low levels of gene 3 expression, but these levels were within the range of the patterns observed in normal placentas. These data suggest that it is the total amount of hCGß gene expression rather than the expression of individual ß genes that is important for the maintenance of normal pregnancy. . A previous study of a first trimester placenta showed that all 6 hCGß genes were expressed; however, 3 were expressed at much higher levels than the others (2). hCGß gene 5 was found to account for 64% of the total hCGß expression. Genes 3 and 8 were each responsible for 18% of the total expression, and hCGß gene 7 accounted for less than 2% of the total expression. Genes 1 and 2 were also detected, but at levels of less than 1% of the total. In our study, we examined 27 placentas from 6–16 weeks gestational age to determine whether this pattern of hCGß expression was typical of a normal pregnancy and whether the expression pattern varied with gestational age.
hCGß apparently evolved from gene duplication events of the LHß gene. Although the nucleotide sequences of hCGß and LHß are 94% homologous (4), at the amino acid level there is 85% homology between hCGß and LHß over the first 114 of 121 amino acids of LHß (5). There are slight differences in the promoter regions of the genes, which may account for their differential tissue expression, i.e. LHß expression in the pituitary and hCGß expression in the placenta.
Genes 5, 3, and 8 give rise to identical proteins. The gene 7 product differs by one amino acid from the others, a Pro to Met at codon 4 (3). Genes 1 and 2, due to 5'-splice differences, give rise to unique open reading frames that may result in proteins with functions different from those of the other hCGß gene proteins (2). There are also differences among the individual hCGß genes in the promoter regions that may play a role in the differences in expression among these genes. We were interested in determining whether the individual hCGß genes were up- or down-regulated during developmental stages in early pregnancy, perhaps yielding an expression pattern unique to each phase of early embryo growth. To begin to answer this question, we obtained placentas of various gestational ages and screened for hCGß expression of genes 5, 3, 8, and 7.
It is also possible that unusual hCGß expression patterns play a role in the etiology of some clinical conditions, or that they could serve as unique biochemical markers in such cases as spontaneous abortion, blighted ovum, hydatidiform mole, choriocarcinoma, or ectopic hCG-producing cancers. For example, bladder cancers were recently found to produce hCGß, and the level of hCGß gene expression from genes 5, 3, and 8 correlated with the stage of the tumor (6). Transcription levels of these three hCGß genes increased with the stage of disease, whereas only ß gene 7 was expressed in normal urothelial tissue (6).
In the study reported here, the levels of expression of ß genes 5, 3, 8, and 7 were examined in 27 normal placentas of 6–16 weeks gestational age as well as in tissue samples obtained from spontaneous abortion, blighted ova, hydatidiform mole, and cultured JAR choriocarcinoma cells. In most of the normal placentas, gene 5 was the most highly transcribed gene, but there was significant variation in the percentage that gene 5 contributed to the total hCGß gene transcription. There were also highly variable contributions of genes 3 and 8 to the total amount of hCGß messenger RNA (mRNA) produced. Moreover, although the overall patterns of hCGß gene expression varied among the normal placentas, there was no correlation with gestational age. The pattern of expression among the abnormal tissues was not unique and was also seen in 1 or more of the normal placentas. These data suggest that a functional level of hCGß subunit can be obtained by expression of various ß genes and that it is the total level of hCGß produced rather than the expression of individual ß genes that is important for maintenance of early pregnancy.
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