Estrogen In Epithelial Cells Research Articles

Avian SERPINB12 expression in the avian oviduct is regulated by estrogen and up-regulated in epithelial cell-derived ovarian carcinomas of laying hens.

Serine protease inhibitors (SERPINs) are involved in a variety of biological processes such as blood clotting, angiogenesis, immune system, and embryogenesis. Although, of these, SERPINB12 is identified as the latest member of clade B in humans, little is known of it in chickens. Thus, in this study, we investigated SERPINB12 expression profiles in various tissues of chickens and focused on effects of steroid hormone regulation of its expression. In the chicken oviduct, SERPINB12 mRNA and protein are abundant in the luminal (LE) and glandular (GE) epithelia of the magnum in response to endogenous or exogenous estrogen. Furthermore, SERPINB12 mRNA and protein increase significantly in GE of cancerous ovaries of laying hens with epithelia-derived ovarian cancer. Collectively, these results indicate that SERPINB12 is a novel estrogen-stimulated gene that is up-regulated by estrogen in epithelial cells of the chicken oviduct and that it is a potential biomarker for early detection of ovarian carcinomas in laying hens and women.

Hormonal regulation of beta-catenin during development of the avian oviduct and its expression in epithelial cell-derived ovarian carcinogenesis

Beta-catenin (CTNNB1) is a dual function molecule that acts as a key component of the cadherin complex and WNT signaling pathway. It has a crucial role in embryogenesis, tumorigenesis, angiogenesis and progression of metastasis. Recently, it has been suggested that the CTNNB1 complex is a major regulator of development of the mouse oviduct and uterus. However, little is known about the CTNNB1 gene in chickens. Therefore, in this study, we focused on the CTNNB1 gene in the chicken reproductive tract and hormonal control of its expression in the chicken oviduct. CTNNB1 was localized specifically to the luminal and glandular epithelium of the four segments of chicken oviduct and DES (diethylstilbestrol, a synthetic non-steroidal estrogen) increased its expression primarily in LE of the magnum. In addition, CTNNB1 mRNA and protein were expressed abundantly in glandular epithelium of endometrioid-type ovarian carcinoma, but not in normal ovaries. Moreover, CTNNB1 expression was post-transcriptionally regulated via its 3′-UTR by binding with target miRNAs including miR-217, miR-1467, miR-1623 and miR-1697. Collectively, these results indicate that CTNNB1 is a novel gene regulated by estrogen in epithelial cells of the chicken oviduct and that it is also abundantly expressed in epithelial cells of endometrioid-type ovarian carcinoma suggesting that it could be used as a marker for diagnosis of ovarian cancer in laying hens and women.

Differential expression of secreted phosphoprotein 1 in response to estradiol-17β and in ovarian tumors in chickens

Secreted phosphoprotein 1 (SPP1), a highly phosphorylated protein containing a polyaspartic acid sequence and a conserved RGD motif, plays important roles in physiological processes such as inflammatory responses, calcification, organ development, immune cell function and carcinogenesis. Results of the present study indicate expression of SPP1 mRNA in various organs such as oviduct, small intestine and kidney from chickens, particularly in the glandular epithelium (GE) of the shell gland and, to a lesser extent, in luminal epithelium (LE) of the infundibulum and magnum, and GE of the isthmus of the oviduct. We determined that DES (diethylstilbestrol, a synthetic nonsteroidal estrogen) decreases SPP1 expression in the oviduct and that SPP1 mRNA and protein are significantly more abundant in GE of ovarian endometrioid carcinoma, but not the other cancerous and normal ovaries of hens. Further, microRNA-140 was discovered to influence SPP1 expression via its 3′-UTR which suggests that post-transcriptional regulation influences SPP1 expression in chickens. Collectively, results of this study indicate that SPP1 is novel in that its expression is down-regulated by estrogen in epithelial cells of the chicken oviduct and that it is up-regulated in chicken ovarian endometrioid tumor that could be used for monitoring effects of therapies for this disease in laying hens.

Cell type-specific induction of cyclin D and cyclin-dependent kinase inhibitor p27 kip1 expression by estrogen in rat endometrium

Cyclins, cyclin-dependent kinases (CDKs) and the CDK inhibitor p27 kip1 are known to be involved in the regulation of G 1/S phase transition by estrogen in the rodent endometrium. Little is known, however, of the cell-specific location and regulation of these proteins during this process, or the way they mediate the differential effect of estrogen in the epithelium and stroma of the endometrium. Here we studied the cell-specific regulation of D-type cyclin (D 1–3), of cyclin A and E, of CDK 2 and p27 kip1 by 17β-estradiol in the endometrium of ovariectomized rats. Time-course changes in these proteins in the endometrium of ovariectomized rats were examined by immunohistochemistry at 2, 4, 8, 12, 20, 28 and 32 h after estrogen stimulation. The expression of proliferation cell nuclear antigen (PCNA) was also studied as a marker of proliferating cells. As expected from previous studies, all the proteins investigated were up-regulated by estrogen, with peak times from 8 to 32 h. The induction of cyclin D 1 is predominant in the glandular epithelium, whereas cyclin D 3 increases mainly in the luminal epithelium. The up-regulation of p27 kip1 is restricted to stromal cells with a ‘gradient-like’ expression pattern, in which the sub-epithelial (functional) layer showed stronger staining than the basal layer. The differential regulation of cyclins and p27 kip1 in the epithelium and stroma of the endometrium appear indicative of distinct actions of estrogen in different cell types in the uterus, as D-type cyclins mediate the proliferative effect of estrogen in epithelial cells while p27 kip1 might help prevent the same effect in the stroma.

Genotoxic effects of estrogens in epithelial cells from the neonatal mouse uterine cervix: Modifications by metabolic modifiers

Epithelium from the neonatal mouse uterine cervix and uppermost part of vagina was cultured in vitro. The culture medium was supplemented with 17 beta-estradiol (E2; 10(-6)-10(-5) M) or diethylstilbestrol (DES; 10(-8)-10(-5) M) alone or in combination with different metabolic modifiers (alpha-naphthoflavone, beta-naphthoflavone, phenobarbital, metyrapone, indomethacin) with postulated activating or inhibitory effects on DES metabolizing enzymes (cytochrome P-448- and P-450-dependent microsomal monooxidases, prostaglandin cyclooxygenase). E2 at 10(-5) M and DES at 10(-6) and 10(-5) M concentrations increased the incidence of cells with a high number of sister chromatid exchanges (high-frequency chromatid exchange cells, HFCEC). Indomethacin partially depressed DES-induced HFCEC, whereas the incidence was increased by alpha-naphthoflavone, which may be a result of stimulation of the fetal type of P-448-dependent enzyme activity or of DES increasing the metabolic activation of alpha-naphthoflavone. Phenobarbital and beta-naphthoflavone did not affect the incidence of DES-induced HFCEC. Metyrapone alone induced the highest incidence of HFCEC observed in this study, and this effect was inactivated by phenobarbital and/or DES. The mechanisms behind these results are discussed. This study shows that E2 and DES have a genotoxic effect (sister chromatid exchanges) in vitro in epithelial cells from the same target organ as in which epithelial aberrations occur after in vivo estrogen treatment in the neonatal period. The difference in incidence of tetraploid cells between stroma and epithelium is stressed (less than 5% vs. 16-47% depending on experimental group).