oxytocin and Adenocarcinoma

Topics: Adenocarcinoma; Adrenocorticotropic Hormone; Arginine Vasopressin; Calcitonin; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Chorionic Gonadotropin; Growth Hormone; Hormones, Ectopic; Humans; Lung Neoplasms; Neurophysins; Oxytocin; Parathyroid Hormone

The strong male predominance in oesophageal adenocarcinoma (OAC) and Barrett's oesophagus (BO) continues to puzzle. Hormonal influence, e.g. oestrogen or oxytocin, might contribute.. This genetic-epidemiological study pooled 14 studies from three continents, Australia, Europe, and North America. Polymorphisms in 3 key genes coding for the oestrogen pathway (receptor alpha (ESR1), receptor beta (ESR2), and aromatase (CYP19A1)), and 3 key genes of the oxytocin pathway (the oxytocin receptor (OXTR), oxytocin protein (OXT), and cyclic ADP ribose hydrolase glycoprotein (CD38)), were analysed using a gene-based approach, versatile gene-based test association study (VEGAS).. Among 1508 OAC patients, 2383 BO patients, and 2170 controls, genetic variants within ESR1 were associated with BO in males (p = 0.0058) and an increased risk of OAC and BO combined in males (p = 0.0023). Genetic variants within OXTR were associated with an increased risk of BO in both sexes combined (p = 0.0035) and in males (p = 0.0012). We followed up these suggestive findings in a further smaller data set, but found no replication. There were no significant associations between the other 4 genes studied and risk of OAC, BO, separately on in combination, in males and females combined or in males only.. Genetic variants in the oestrogen receptor alpha and the oxytocin receptor may be associated with an increased risk of BO or OAC, but replication in other large samples are needed.

Topics: Adenocarcinoma; ADP-ribosyl Cyclase 1; Aromatase; Barrett Esophagus; Esophageal Neoplasms; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Male; Membrane Glycoproteins; Oxytocin; Polymorphism, Single Nucleotide; Receptors, Oxytocin; Sex Factors

The human testicular receptor 4 (TR4) shares structural homology with members of the nuclear receptor superfamily. Some other members of this superfamily were able to regulate the transcriptional activity of the human oxytocin (OXT) promoter by binding to the first DR0 regulatory site. However, little investigation was conducted systematically in the study of the second dDR4 site of OXT proximal promoter, and the relationship between the first and the second sites of OXT promoter. Here, we demonstrated for the first time that TR4 could increase the proximal promoter activity of the human OXT gene via DR0, dDR4, and OXT (both DR0 and dDR4) elements, respectively. TR4 might induce OXT gene expression through the OXT element in a dose-dependent manner. However, there is no synergistic effect between DR0 and dDR4 elements during TR4 transactivation. Taken together, these results suggested that TR4 should be one of important regulators of OXT gene expression.

Topics: Adenocarcinoma; Cell Line, Tumor; Humans; Lung Neoplasms; Nuclear Proteins; Oxytocin; Promoter Regions, Genetic; Repressor Proteins; Transcriptional Activation

Cell-surface oxytocinase inactivates oxytocin and regulates oxytocin stimulation. We reported that oxytocinase in human endometrial epithelial cells was secreted from the cell membrane in the mid-secretory phase and disappeared from the cell surface. On the other hand, the production in human endometrium of prostaglandins, which play important roles in the reproductive process, has been reported to be upregulated by oxytocin. We investigated whether progesterone affects cell-surface oxytocinase and oxytocin-induced prostaglandin E2 (PGE2) production in vitro. Progesterone induced secretion of oxytocinase into the culture medium, which resulted in a decrease in cell-surface oxytocinase. Production of PGE2 was increased slightly by oxytocin without progesterone, and significantly with progesterone. The inhibition of oxytocinase activity by amastatin had a similar effect to the loss of cell-surface oxytocinase caused by progesterone. It is therefore likely that the cell-surface oxytocinase of endometrial epithelial cells modified by progesterone plays an important role in the function of the human endometrium through PGE2.

Topics: Adenocarcinoma; Adult; Cell Line, Tumor; Cystinyl Aminopeptidase; Dinoprostone; Endometrial Neoplasms; Endometrium; Epithelial Cells; Female; Humans; Membrane Proteins; Oxytocin; Peptides; Progesterone; Protease Inhibitors; Statistics, Nonparametric

Transcriptional activation of the gene coding for the neuropeptide hormone oxytocin by oestrogens does not follow the classical model of oestrogen receptor action. The oxytocin promoter does not contain an oestrogen response element (ERE), but instead a high-affinity binding site for nuclear orphan receptors. In the present study, the oestrogen-dependent up-regulation of the bovine oxytocin promoter is investigated in MDA-MB 231 cells. Control by oestrogen is shown to be dependent on the integrity of the nuclear orphan receptor binding site and the presence of ligand-activated oestrogen receptor, but independent of oestrogen receptor binding to DNA. Partial agonists tamoxifen and raloxifen and the pure antagonist ICI 182 780 all show agonistic activities on transcription, while exhibiting normal binding affinities to oestrogen receptor (ER)alpha. Nuclear orphan receptors oestrogen receptor-related receptor alpha (ERRalpha) and germ cell nuclear factor (GCNF) are expressed to significant levels in MDA-MB 231 cells. Binding of ERRalpha to the oxytocin promoter binding site can be demonstrated, suggesting the involvement of this nuclear orphan receptor in oestrogen-dependent up-regulation. The oestrogenic stimulation of the oxytocin promoter apparently is dependent on the stimulation of the transcriptional activity of this nuclear orphan receptor by ERK-1/ERK-2 mitogen-activated protein kinases (MAP kinases). This novel nonclassical mechanism of oestrogen action most probably is not restricted to the regulation of neuropeptide hormone expression, but may further contribute to the multitude of tissue-specific effects of oestrogenic substances.

Topics: Adenocarcinoma; Animals; Breast Neoplasms; Cattle; Cell Line, Tumor; Epithelial Cells; ERRalpha Estrogen-Related Receptor; Estrogen Antagonists; Estrogens; Gene Expression Regulation; Humans; Oxytocin; Receptors, Cytoplasmic and Nuclear; Receptors, Estrogen; Response Elements; Signal Transduction; Transcriptional Activation; Up-Regulation

Oxytocin has been implicated in the regulation of prostate growth. However, the cellular localisation of oxytocin in the normal and diseased human prostate is not known. Oxytocin, oxytocin-associated neurophysin and oxytocin receptor were detected by immunohistochemistry in tissues from patients undergoing routine prostatectomy and in normal human prostate epithelial and stromal cell lines. Western blot analysis detected a single band at 14 kDa with neurophysin antiserum and a 66-kDa band with oxytocin receptor antiserum in epithelial and stromal cell lines. Similar sized bands were also detected in extracts of hyperplastic and adenocarcinomic prostate tissues. Oxytocin, oxytocin-associated neurophysin and oxytocin receptor were present in stromal and epithelial cell lines and in tissue from patients with benign prostatic hyperplasia. The peptides were localised predominantly to the epithelial cells, although discrete areas of stromal staining were also observed. There was a significant difference in the intensity of oxytocin-staining between tissue displaying benign prostatic hyperplasia and invasive carcinoma, with less immunoreactivity being present in the malignant epithelial cells. Thus, oxytocin and its neurophysin and receptor are present in epithelial and stromal cells of the human prostate. Oxytocin expression is reduced with tumour progression and may provide a marker for invasive disease.

Topics: Adenocarcinoma; Blotting, Western; Cell Line; Humans; Immunohistochemistry; Male; Neurophysins; Oxytocin; Prostate; Prostatic Neoplasms; Receptors, Oxytocin; Stromal Cells

Oxytocin (OT) was reported to inhibit the proliferation of various neoplastic tissues and cells, however, the regulation system remains unclear. This study examined the role of OT and its regulatory ability in endometrial adenocarcinoma.. To investigate the possible function of placental leucine aminopeptidase (P-LAP) in endometrial adenocarcinoma, we transfected P-LAP cDNA into A-MEC cells, showing the lowest enzyme activity of P-LAP. Also we examined P-LAP protein expression in human endometrial adenocarcinoma.. We demonstrated the presence of P-LAP, which is identical to cystine aminopeptidase as oxytocinase, in human endometrial adenocarcinoma tissues and found that the expression of P-LAP increase with advances in the grade. Exposure of endometrial adenocarcinoma cell lines to OT caused dose- and time-dependent inhibition of growth. Treatment with 10(-7) M OT for 72 h reduced cell growth by 62, 25, and 30% in A-MEC, HEC1A, and Ishikawa cells, respectively. P-LAP-transfectant cells not only partially recovered from OT-induced growth inhibition but also showed a higher growth rate than parental cells under condition without OT. An OT receptor antagonist and a protein kinase A inhibitor blocked OT-induced growth inhibition in A-MEC and A-MEC-pc cells but not in A-MEC-LAP cells.. These findings suggested that P-LAP might be functionally positive on carcinoma cell growth by degrading suppressive peptides such as OT.

Topics: Adenocarcinoma; Blotting, Western; Cell Division; Cell Line, Tumor; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cystinyl Aminopeptidase; DNA, Complementary; Dose-Response Relationship, Drug; Endometrial Neoplasms; Female; Humans; Immunoblotting; Immunohistochemistry; Oxytocin; Peptides; Plasmids; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Transfection

Oxytocin receptors (OTRs) are expressed in endometrial cells and oxytocin (OT) participates in endometrial functions. In cancers derived from other OT target tissues, such as breast and neural tissues, the expression of OTRs and the antiproliferative effect of OT on cancer cells has been previously observed. This study was therefore designed to search for OTR expression and the OT effect in endometrial carcinomas. To demonstrate the presence and the location of OTRs and OTR mRNA immunocytochemical, reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ hybridization (ISH) procedures were employed in a series of human adenocarcinomas of the endometrium. Using an anti-OTR monoclonal antibody (IF3), OTRs were demonstrated in the large majority of endometrial carcinomas (82%), with a pattern of positivity varying from diffuse to focal, according to tumour differentiation. The OTR gene was demonstrated in 78% of the cases by RT-PCR and its presence was confirmed in selected cases by ISH. Moreover, in a human endometrial carcinoma cell line (COLO 684) OTR was demonstrated by immunofluorescence and RT-PCR and it was observed that OT treatment (10(-11)-10(-7) M) significantly inhibited cell proliferation. Neither toxic effects nor apoptosis were induced by OT treatment. The addition of an inhibitor of protein kinase A (PKA) to the culture medium abolished the antiproliferative effect of OT, suggesting that cAMP via PKA could be the intracellular mediator of the OT effect, as previously observed in breast and neural tumours. In conclusion, this study presents evidence of OTR expression in human endometrial carcinomas and of an OT antiproliferative effect on human endometrial cancer cells in vitro. It is further suggested that OT and OTR may be involved in the regulation of endometrial cells, not only in physiological conditions but also in a neoplastic context.

Topics: Adenocarcinoma; Apoptosis; Cell Division; Dose-Response Relationship, Drug; Endometrial Neoplasms; Female; Humans; Immunohistochemistry; In Situ Hybridization; Neoplasm Proteins; Oxytocin; Receptors, Oxytocin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

In previous studies we have demonstrated the high incidence of vasopressin gene expression as a characteristic feature of small-cell carcinoma of the lung. In the present study we examined expression of this gene in non-neuroendocrine tumors to determine if vasopressin production is a common feature of all lung tumors. We carried out the immunohistochemical evaluation of 22 non-neuroendocrine tumors (12 adenocarcinomas and 10 squamous-cell carcinomas) with antibodies to vasopressin, to oxytocin, and to their related neurophysins. The antibody preparations directed against vasopressin, oxytocin, or oxytocin-associated human neurophysin did not react with any of the tumors examined. Of two monoclonal antibodies to vasopressin-associated human neurophysin used, one did not react with any of the tumors, while the other stained neoplastic cells in only one adenocarcinoma and one squamous-cell carcinoma. These findings, taken with previous reports, indicate that among lung carcinomas, a high incidence of vasopressin/oxytocin gene expression is confined to neuroendocrine tumors.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Carcinoma, Squamous Cell; Gene Expression; Humans; Immunoenzyme Techniques; Lung Neoplasms; Neurophysins; Oxytocin; Vasopressins

At diagnosis, 65% of 103 patients with small cell carcinoma of the lung were found to have elevated plasma concentrations of vasopressin-associated human neurophysin (VP-HNP), oxytocin-associated human neurophysin (OT-HNP), or both, which were thought to be related to tumor secretion of these proteins. The remainder of patients were designated as nonsecretors (24%) or possible secretors (11%), depending upon plasma concentration of the neurophysins prior to therapy. There was a significantly higher percentage of secretors among patients with extensive disease (82%) than among those with limited disease (40%) (P = 0.001). However, within each stage group, there was no correlation between secretory status and response to therapy, survival, or histologic subtype. In addition, patients who initially were nonsecretors or possible secretors maintained this status throughout the course of disease remission and subsequent relapse. These findings suggest the possibility of biochemical differences between tumors which present as limited disease and those which present as extensive disease. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) was infrequent in limited disease but was present in 33% of patients with extensive disease. SIADH was not seen without VP-HNP elevation; however, with extensive disease, 49% of patients with elevated VP-HNP had SIADH. In contrast, elevated plasma concentrations of the neurophysins were seen in only 19.6% of 56 patients with non-small cell carcinoma of the lung. The levels were in general lower than those in patients with small cell carcinoma and were seen at approximately equal frequencies in each major cellular subtype.

Topics: Adenocarcinoma; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Humans; Inappropriate ADH Syndrome; Lung Neoplasms; Neurophysins; Oxytocin; Prognosis; Vasopressins

Topics: Adenocarcinoma; Animals; Carcinoma, Bronchogenic; Choriocarcinoma; Culture Media; Diuresis; Female; In Vitro Techniques; Liver; Liver Neoplasms; Lung Neoplasms; Neoplasm Metastasis; Oxytocin; Pancreatic Neoplasms; Pregnancy; Rats; Recurrence; Uterine Neoplasms; Vasopressins

Topics: Abortion, Induced; Adenocarcinoma; Blood Coagulation Disorders; Carcinoma in Situ; Carcinoma, Squamous Cell; Curettage; Dilatation; Embryo, Mammalian; Female; Fetus; Gestational Age; Humans; Hypernatremia; Hypertonic Solutions; Lymphatic Metastasis; Oxytocin; Pregnancy; Prognosis; Thromboplastin; United States; Uterine Cervical Neoplasms; Uterine Neoplasms; Vaginal Smears

Topics: Adenocarcinoma; Animals; Biological Assay; Carcinoma, Bronchogenic; Chickens; Humans; Hyponatremia; Lung Neoplasms; Male; Methods; Middle Aged; Neoplasm Metastasis; Neoplasms, Multiple Primary; Osmolar Concentration; Oxytocin; Pancreatic Neoplasms; Pneumonectomy; Rabbits; Radioimmunoassay; Rats; Vasopressins