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PubMed1994

Human chorionic gonadotropin beta-subunit synthesis by undifferentiated urothelial carcinoma with syncytiotrophoblastic differentiation.

An undifferentiated deeply invasive ureteral carcinoma with syncytiotrophoblastic differentiation was analyzed for the synthesis of human chorionic gonadotropin beta-subunit by immunohistochemistry and Northern blot analysis. Human chorionic gonadotropin beta-subunit was localized immunohistochemically to syncytiotrophoblastic cells and scattered mononuclear tumor cells. Human chorionic gonadotropin beta-subunit gene was expressed at a high level by Northern blot analysis. To our knowledge, this is the first report demonstrating the synthesis of human chorionic gonadotropin beta-subunit at the transcriptional level in a urothelial carcinoma.

Aged↗
PubMed1997

[Eutopic and ectopic production of glycoprotein hormones alpha and beta subunits].

Human chorionic gonadotropin (hCG) is a glycoprotein composed of two subunits, alpha and beta, linked together by a covalent bond. Ectopic production of hCG has been described in various histological types of cancer. Actually, these malignant tumors predominantly secrete the free beta subunit (hCG beta) and not hCG. Production of free hCG beta is especially found in patients with bladder, pancreas, uterine and lung tumors. In patients with neuroendocrine tumors, serum levels of free hCG beta are higher in gastrointestinal-pancreatic and lung tumors. The significance of ectopic production of hCG beta--epiphenomena or intrinsic biological role--remains unknown. Several reports on the similar structure of hCG beta and certain growth factors suggest that free hCG beta could have an effect on cell proliferation. Increased serum levels of the free alpha subunit are found mainly in patients with neuroendocrine tumors localized in the gut or lung. Serum levels may also be raised in patients with a pituitary tumor, but such production is often associated with a rise in other pituitary hormones. The free alpha subunit plays a role in embryon development and would stimulate production of prolactin by decidual cells. The free alpha subunit may also play a role in tumor growth.

Chorionic Gonadotropin, beta Subunit, Human↗
PubMed1990

Prediction of residual trophoblastic tissue in first-trimester abortions and low levels of human chorionic gonadotropin beta-subunit.

The clinical data and the histologic report of curettage specimens of 174 patients with first-trimester abortion and human chorionic gonadotropin beta-subunit less than 500 mIU/ml were reviewed. In only 22 (12.6%) were chorionic villi histologically reported. A multivariate analysis showed that increased log human chorionic gonadotropin beta-subunit levels within the range of 20 to 500 mIU/ml, intrauterine tissue demonstrated by ultrasonography, higher gestational age, and active bleeding were significant predictive variables for the presence of villi in curettage specimens. A mathematical formula and a clinical scoring system for the prediction of residual villi in these cases were devised and were applied to the data of our study group. The sensitivity, false-negative rate, and specificity of the scoring system were 90.9%, 2.2%, and 59.2%, respectively; however, the false-positive rate was 75.6%. By use of this scoring system in patients with first-trimester abortion and low human chorionic gonadotropin beta-subunit level, the presence of villi in curettage specimens can thus be predicted with a high sensitivity and as many as 60% of curettage procedures might be prevented.

Abortion, Induced↗
PubMed1987

Radioimmunoassay of the serum free beta-subunit of human chorionic gonadotropin in trophoblastic disease.

We developed a RIA specific for the free beta hCG employing anti-beta hCG monoclonal antibody 1D12. This RIA was highly sensitive to free beta hCG; the minimum detectable concentration was 0.4 ng/ml. alpha hCG, LH, beta LH, and FSH had little effect in the assay; the cross-reactivity of hCG was about 4%. Using this RIA, we measured serum free beta hCG concentrations in 38 normal pregnant women and 72 untreated patients with 3 types of trophoblastic disease: hydatidiform mole (n = 15), invasive mole (n = 29), and choriocarcinoma (n = 28). All of these samples were simultaneously assayed for hCG by RIA. In normal pregnant women, serum hCG changed as pregnancy progressed, but serum free beta hCG was not detected at any time. In contrast, serum free beta hCG was measurable in the majority of patients with trophoblastic disease. Strong correlations were found between the concentration of free beta hCG and that of hCG in each type of trophoblastic diseases. The mean free beta hCG to hCG ratio was lowest for hydatidiform mole and highest for choriocarcinoma, and the difference between the ratios in these 2 groups was statistically significant. Serial measurements in 7 patients with trophoblastic disease failed to reveal remarkable changes in the free beta hCG to hCG ratio throughout their clinical course. We conclude that the production of free beta hCG increases with the immaturity of the trophoblastic cell, and the degree of differentiation of trophoblastic cells may be reflected by the free beta hCG to hCG ratio.

Adult↗
PubMed1992

Monoclonal antibodies to the free beta-subunit of human chorionic gonadotropin define three distinct antigenic domains and distinguish between intact and nicked molecules.

The present study was designed to characterize monoclonal antibodies (mAbs) specific for the free beta-subunit of hCG (free hCG beta), to develop two-site immunoradiometric assays (m-IRMAs) specific for free hCG beta, and to study the reactivities of various molecular forms of hCG beta in these assays. We attempted first to delineate the antigenic regions present specifically on the free hCG beta by studying the binding pattern of seven mAbs directed preferentially to hCG beta, designated FBT11, P8E, P10F, HB2, P5D, P5H, and INN-64. Competitive inhibition experiments performed by RIA demonstrated the specificity of these mAbs for the free hCG beta as noncross-reacting with the beta-subunit of human (h) LH beta. m-IRMAs were used to analyze the arrangement of epitopes on hCG beta. Experiments performed with the seven mAbs used either as capture antibodies or radiolabeled indicators confirmed the specificity of the seven mAbs for the free hCG beta, and that mAbs FBT11, P8E, and P10F bound to equine LH beta (eLH beta), but did not bind to a fragment of hCG beta called the beta-core fragment (beta CF). These antibodies defined an antigenic domain identified as A. In contrast, mAb HB2 bound neither to eLH beta (e beta) nor to beta CF and was directed to domain B (e beta negative, beta CF negative). Finally, mAbs P5D, P5H, and INN-64 bound to beta CF, but did not bind to eLH beta, and defined a third domain identified as C (e beta negative, beta CF positive). Collectively, these results demonstrate that at least six antigenic domains are present on the free hCG beta and that a limited set of amino acids was shared among these domains; domains A, B, and C are present only on the free beta-subunit, while three other domains recognized by mAbs FB19, FBT10, and 518B7 are present on both free hCG beta and hCG. Thus, most of the surface of the hCG beta appears to be antigenic and accessible to antibody binding. Three different m-IRMAs specific for free hCG beta were then constructed using either mAb FBT11 (domain A) or HB2 (domain B). The study of the reactivities of various molecular forms of hCG beta in these assays demonstrated that the recognition of hCG beta forms nicked at position 43 (beta 43), 44, and/or 51 (beta 44/51) varied between assays.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗
PubMed1990

Occurrence of fragmentation of free and combined forms of the beta-subunit of human chorionic gonadotropin.

In an attempt to further study various fragments of free and combined forms of hCG beta present in biological fluids, we performed one- and two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis, followed by Western immunoblotting using antipeptide antibodies directed to the hCG beta-(111-116) portion (monoclonal antibody FB12) antiserum to the hCG beta(8-16) portion or antiserum which was specific for fragments ending at residue 47. Results observed in a crude preparation of urinary hCG demonstrated that in addition to the carboxyl-terminal part of the reduced hCG beta nicked subunit (beta NS) [hCG beta-(48-145)], three other fragments of mol wt 18,000 (F1), 16,500 (F2), and 12,000 (F3) were detectable after cleavage of disulfide bonds. Both the immunoreactivity pattern and peptide sequencing revealed that the F1 fragment was constituted of the hCG beta-(1-47) sequence, whereas the F2 fragment comprised the 6-47 portion. We then studied the beta NS in urine from either pregnant women or four patients with choriocarcinomas. Results showed that both hCG and the free beta-subunit contained beta NS. Furthermore, free hCG beta present in those urine samples appeared to be extensively, if not totally, nicked. Results observed in urine were confirmed using separation of hCG from its beta-subunit by a two-step chromatography procedure, identification of hCG and hCG beta immunoreactive peaks by specific monoclonal immunoradiometric assay, and analysis of resulting preparations by one-dimensional electrophoresis under reducing conditions, followed by Western immunoblotting with FB12. This latter protocol was also used to investigate the presence of beta NS in sera of four patients with choriocarcinoma tumors. In those sera, hCG appeared to be nicked. This study demonstrates that the beta-subunit of hCG is modified by multiple fragmentations.

Amino Acid Sequence↗
PubMed1995

Human chorionic gonadotropin-beta subunit gene expression in cultured human fetal and cancer cells of different types and origins.

BACKGROUND: The authors' previous investigations using living cultured human cancer cells and cells isolated from cancer tissues, analytical flow cytometry, and monoclonal antibodies directed to epitopes located in five different sites of the human chorionic gonadotropin (hCG) molecule, identified the presence of membrane-associated hCG, its subunits and fragments, by cells from all cancers, irrespective of type and origin, indicating that the expression of these sialoglycoproteins is a common phenotypic characteristic of cancer. Although benign neoplasms do not express these compounds, cultured human embryonic and fetal cells also express the same materials. To corroborate these findings, five fetal cell lines and 28 cancer cell lines were randomly selected from those previously studied, to determine the presence of translatable levels of hCG-beta (hCG beta) mRNA. METHODS: All cell lines were grown under identical conditions. Determination of hCG beta mRNA was made by extracting the total RNA from the cells, followed by synthesis of cDNA with RNase H- reverse transcriptase and polymerase chain reaction amplification using specific hCG beta-luteinizing hormone-beta (hLH beta) primers. The presence of amplified hCG beta cDNA was corroborated by hybridization of the product with an hCG beta-specific oligonucleotide and Southern blot analyses of the hybridization products. Gestational choriocarcinoma cells and HeLa adenocarcinoma of cervical cells, known producers of biologically active hCG, were positive control subjects, and human pituitary cells were used as negative control subjects. RESULTS: The results showed single and multiple hCG beta gene activation by the fetal cells and the different types of cancer, indicating that at any given time, there is the possibility of activation of as many as four genes of the six genes of the hCG beta-hLH beta gene cluster, even though alternative gene splicing cannot be ruled out. CONCLUSIONS: In addition to the authors' previous findings, the results of these studies support the concept that cancer is a problem of development and differentiation, and, to the authors' knowledge, prove definitively for the first time that synthesis and expression of hCG, its subunits, and its fragments, is a common biochemical denominator of cancer, providing the scientific basis for studies of its prevention and/or control by active and/or passive immunization against these sialoglycoproteins.

Base Sequence↗
PubMed2003

Expression of the free beta-subunit of human chorionic gonadotropin in renal cell carcinoma: prognostic study on tissue and serum.

Expression of the free beta-subunit of human chorionic gonadotropin (hCGbeta) in malignant tumors is frequently associated with aggressive disease. We have shown previously that the pretreatment serum concentration of hCGbeta is an independent prognostic variable in patients with renal cell carcinoma (RCC). We now compare the serum levels with the expression of hCGbeta antigen and mRNA in tumor tissue and studied whether these are associated with the clinical outcome. Serum samples were collected before surgery from patients with RCC (n = 256) and from 84 apparently healthy controls. HCGbeta in serum was measured by a time-resolved immunofluorometric assay. Tissue expression was detected by immunohistochemical staining of a tissue microarray (TMA) comprising 229 samples, and in selected cases by reverse transcription polymerase chain reaction (RT-PCR) of hCGbeta mRNA (n = 20) from tumor tissue. The prognostic value of hCGbeta in serum and tissue and the association with usual clinicopathological variables was analyzed by the Kaplan-Meier method, the log-rank test, Cox multiple hazard regression, Mann-Whitney U-test or Kruskal-Wallis test. The serum concentrations of hCGbeta were increased in 27% of the RCC patients and patients with increased hCGbeta levels had significantly shorter survival time than those with levels below the median (cut-off 1.2 pmol l(-1), p = 0.0044). HCGbeta antigen was detected in 15% (35 of 229) of the tumors by immunohistochemistry, and hCGbeta mRNA in 8 of 20 samples (40%) by RT-PCR. Tissue positivity for hCGbeta antigen was not associated significantly with mRNA expression, serum concentrations of hCGbeta or survival. In multivariate analysis tumor stage, grade, size and serum hCGbeta were independent prognostic variables. The serum concentration of hCGbeta is an independent prognostic variable in RCC. Tissue expression of hCGbeta detected by immunohistochemistry occurs in 15% of RCCs but it is not significantly associated with prognosis. Expression at the mRNA level seems to be associated with other predictors of adverse outcome.

Adult↗
PubMed2006

Analysis of the three dimensional structure of the CXGXC motif in the CMGCC and CAGYC regions of alpha-and beta-subunits of human chorionic gonadotropin: importance of glycine residue (G) in the motif.

The three dimensional structures of the C(1)X(2)G (3)(X(3))X(4)C(5) motif of hCG, which is considered to be important for noncovalent assembly of the alpha- and beta-subunits of glycoprotein hormones were analyzed to assess the importance of glycine (Gly) (G) at site X(3) in the motif by the conformational energy calculation using computational procedures. In the C(1)M(2)G (3)(X(3))C(4)C(5) motif of the alpha-subunit, Ramachandran plot analysis showing the allowed area of the dihedral angles demonstrated that only a Gly residue was allowed at site X(3). In calculating collision with surrounding atoms as a monomer the possible main chain models of the C(1)A(2)G(3)(X(3))Y(4)C(5) motif in the beta-subunit showed that only alanine (Ala) (A) or Gly at site X(3) is allowed to alleviate the collision with the cysteine (Cys) (C) residues which form a disulfide bridge. A mutant of the beta-subunit with the C(1)A(2)A(3)(X(3))Y(4)C(5) motif (Ala at site X(3)) may not compose a heterodimer with the alpha-subunit because of interference of intermolecular hydrogen bond formation. These findings indicate that the Gly residue at site X(3) (G(3)) in the motif is essential for heterodimer formation of glycoprotein hormones. The significance of similar motifs found in various human proteins other than glycoprotein hormones was suggested.

Alanine↗
PubMed2006

[Dynamic monitoring of serum human chorionic gonadotropin beta-subunit levels for early diagnosis of ectopic pregnancy].

OBJECTIVE: To assess the value of monitoring serum human chorionic gonadotropin beta-subunit (beta-HCG) level changes in early diagnosis of ectopic pregnancy. METHODS: Totalling 106 cases of ectopic pregnancy and 69 cases of threatened abortion were included in the study. Blood samples were collected to examine beta-HCG levels, which was repeated 2-3 days later. RESULTS: Initial serum beta-HCG levels of the women with ectopic pregnancy and different were significantly lower than those in women with threatened abortion (P<0.05), and the increment rate of serum beta-HCG in the former was also significantly lower (P<0.05). CONCLUSION: Compared with single-time serum beta-HCG detection, dynamic monitoring of serum beta-HCG provides more important and reliable evidence for early diagnosis of ectopic pregnancy. Transvaginal ultrasonography and in should also be considered in the clinical analysis.

Adult↗
PubMed1999

Crystal structure of a ternary complex between human chorionic gonadotropin (hCG) and two Fv fragments specific for the alpha and beta-subunits.

Human chorionic gonadotropin (hCG), is a placental hormone which exerts its major effect by stimulating progesterone production, crucially sustaining the early weeks of pregnancy. Detection of hCG with specific monoclonal antibodies (mAbs) has become the chosen means for pregnancy diagnosis. We have used antibody Fv fragments derived from two high-affinity mAbs, one against the alpha and the other against the beta-hCG subunit to enable the crystallisation of intact or desialylated hCG. Crystals of a ternary complex composed of Fv anti-alpha/hCG/Fv anti-beta were found to diffract to 3.5 A resolution, and the structure was solved by molecular replacement. In the crystal, the two Fvs keep hCG as in a molecular cage, providing good protein-protein contacts and leaving enough space for the saccharides to be accommodated in the cell solvent. The two Fvs were found not to interact directly through their complementary-determining regions with the hCG saccharides, but only with the protein. The hCG structure in the ternary complex was very close to that of the HF partially deglycosylated hormone, thus indicating that neither the saccharides nor the Fvs had any substantial influence on hormone structure.

Amino Acid Sequence↗
PubMed2003

Disulfide bonds Cys(9)-Cys(57), Cys(34)-Cys(88) and Cys(38)-Cys(90) of the beta-subunit of human chorionic gonadotropin are crucial for heterodimer formation with the alpha-subunit: experimental evidence for the conclusions from the crystal structure of hCG.

Human chorionic gonadotropin (hCG) is a heterodimeric glycoprotein hormone essential for the establishment and maintenance of pregnancy. The alpha- and beta-subunits of hCG are highly cross-linked internally by disulfide bonds that seem to stabilize the tertiary structures required for the noncovalent association of the subunits to generate hormonal activity. This paper describes the results of our studies on the role of the disulfide bonds of hCG-beta in heterodimer formation with the alpha-subunit. Six disulfide peptides incorporating each of the six disulfide bonds of hCG-beta were screened, along with their linear counterparts, for their ability to competitively inhibit the recombination of alpha- and beta-subunits. The disulfide peptides Cys (9-57), Cys (34-88) and Cys (38-90) were found to inhibit the alpha/beta recombination whereas the remaining three disulfide peptides viz. Cys (23-72), Cys (26-110) and Cys (93-100) did not exhibit any inhibition activity. Interestingly, none of the linear peptides could inhibit the alpha/beta recombination. Results clearly demonstrate that the disulfide bonds Cys(9)-Cys(57), Cys(34)-Cys(88) and Cys(38)-Cys(90) of the beta-subunit of hCG are crucial for heterodimer formation with the alpha-subunit thus providing experimental confirmation of the conclusions from the crystal structure of the hormone.

Amino Acid Sequence↗
PubMed1990

Treatment of unruptured tubal pregnancy by local injection of methotrexate under transvaginal sonographic control.

Seventeen unruptured tubal gestations were managed on an outpatient basis using local methotrexate (MTX) injection. A single 50-mg dose of MTX was injected into the gestational sac under transvaginal sonographic control. Follow-up included serial assays of the beta-subunit of human chorionic gonadotropin (beta-hCG), clinical and sonographic evaluation. Resolution was obtained in 13 out of 17 patients. The regression curve between days after treatment versus beta-hCG (y = 82.2 - 10.8x + 0.37x2) demonstrated a significant negative correlation (R2 = 0.77; R = 0.88; P less than or equal to 0.02). The mean beta-hCG level on day 15 was 3.2% +/- 3.1% of the initial value. Laparoscopy was performed in 4 patients. Pathological findings suggested that resolution was underway in these four cases despite a slow decline in beta-hCG. No systemic side effects were observed in any of the 17 patients. Long-term follow-up is needed to evaluate tubal patency and reproductive outcome. Our experience suggests that local injection of MTX may be an effective alternative for the treatment of unruptured ectopic pregnancy.

Chorionic Gonadotropin↗
PubMed1991

Ectopic production of beta-subunit of human chorionic gonadotropin in malignant lymphoma.

Ectopic production of human chorionic gonadotropin (HCG) in tumor cells is an uncommon phenomenon that has rarely been documented. The immunoperoxidase method was used to demonstrate the presence of beta-subunit of HCG in malignant lymphoma cases, using paraffin-embedded sections of lymph nodes. 3 of 11 cases of malignant lymphoma (27%) were positively stained with beta-subunit of HCG. All positive cases were T-cell type malignant lymphomas, but all adult T-cell leukemia lymphoma cases did not react with HCG. All B-cell type malignant lymphoma cases were not stained by HCG. Hence, this evidence suggested that beta-subunit of HCG may be useful as a tumor marker in certain malignant lymphoma patients. To the best of our knowledge, production of beta-subunit of HCG in the cytoplasm of malignant lymphoma cells has not been reported.

Adult↗