The roles of estrogen and estrogen receptors in gastrointestinal disease (Review)
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Estrogen is an important sex steroid hormone which serves an important role in the regulation of a number of biological functions, including regulating bone density, brain function, cholesterol mobilization, electrolyte balance, skin physiology, the cardiovascular system, the central nervous system and female reproductive organs. Estrogen exhibits various functions through binding to its specific receptors, estrogen receptor α, estrogen receptor β and G protein‑coupled estrogen receptor 1. In recent years, researchers have demonstrated that estrogen and its receptors serve an important role in the gastrointestinal (GI) tract and contribute to the progression of a number of GI diseases, including gastroesophageal reflux, esophageal cancer, peptic ulcers, gastric cancer, inflammatory bowel disease, irritable bowel syndrome and colon cancer. The aim of this review is to provide an overview of estrogen and its receptors in GI disease, and highlight potential avenues for the prevention and treatment of GI diseases.Estrogen receptor beta
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Abstract Human breast cancer can be divided into a group that contains specific receptor sites for estrogen and a group without such specific estrogen‐binding sites. The presence of specific estrogen receptors in some tumors indicating hormonal dependency has been shown to be of predictive value for endocrine treatment. This would greatly improve therapeutic planning for patients with breast cancer. Tumor tissue from 52 patients was investigated for content of both cytosol estrogen and estrogen receptor. In addition, the total tumor estrogen was also determined in 14 of these tumors. The results of this investigation show two distinct groups: one group containing both estrogen receptor and estrogen and a second group with no receptor but with measurable amount of estrogen. Tumors with estrogen receptors have higher tissue levels of estrogen than tumors without specific estrogen receptor. Even in the absence of estrogen receptor, however, most tumor tissue examined contained a measurable amount of estrogen.
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The aim of this study was to explore the effect of a traditional Chinese medicine (Xiaochaihu Tang, XCHT) on the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 in rats with endometriosis (EMs). A total of 48 specific-pathogen-free (SPF) female Sprague-Dawley (SD) rats were randomly divided into control (n=8) and EMs (n=40) groups. The EMs model was established using a surgical procedure. At 21 days, the rats with EMs were screened and divided into four subgroups (n=8): the model control, low-dose (7.5 g/kg) XCHT-treated, high-dose (15 g/kg) XCHT-treated and gestrinone-treated (0.5 mg/kg) groups. Following 21 days of treatment, the rats were sacrificed. Reverse transcription-polymerase chain reaction (RT-PCR) and western blotting were used to examine the mRNA and protein levels of MMP-2 and MMP-9 in the endometrium. The expression levels of MMP-2 and MMP-9 were significantly increased in the rats with EMs compared with those in normal rats. Moreover, XCHT was able to significantly inhibit the expression of MMP-2 and MMP-9 compared with that in the model control group. In conclusion, XCHT was able to decrease the expression of MMP-2 and MMP-9 in the ectopic endometrium. The present results may provide a potential theoretical basis for the therapy of EMs.
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The proper level of estrogen-estrogen receptor (ER) signaling is important for the maintenance of epithelial homeostasis in the breast. In a previous study we demonstrated that ATBF1, which has been suggested as a tumor suppressor in breast cancer, inhibited estrogen-mediated cell proliferation by selectively competing with AIB1 for binding to the ER. However, the expression of ATBF1 mRNA was shown to positively correlate with ER in breast cancer specimens. We, therefore, examined whether estrogen regulates ATBF1. We demonstrated that estrogen up-regulated the transcription of ATBF1, which was mediated by the direct binding of the ER onto the ATBF1 promoter, and that a half-estrogen-responsive element in the ATBF1 promoter was essential for ER direct binding. Furthermore, we found that estrogen at lower levels increased, but at higher levels decreased the expression of ATBF1 protein, which involved the degradation of ATBF1 protein by the estrogen-responsive proteasome system. ATBF1 protein levels fluctuate with estrogen levels. Although lower levels of estrogen increased ATBF1 protein expression, ATBF1 still inhibited cell proliferation caused by lower levels of estrogen. These findings not only reveal an autoregulatory feedback loop between ATBF1 and estrogen-ER signaling but also suggest that ATBF1 plays a role in both the maintenance of breast epithelial homeostasis and breast tumorigenesis caused by elevated estrogen levels. The proper level of estrogen-estrogen receptor (ER) signaling is important for the maintenance of epithelial homeostasis in the breast. In a previous study we demonstrated that ATBF1, which has been suggested as a tumor suppressor in breast cancer, inhibited estrogen-mediated cell proliferation by selectively competing with AIB1 for binding to the ER. However, the expression of ATBF1 mRNA was shown to positively correlate with ER in breast cancer specimens. We, therefore, examined whether estrogen regulates ATBF1. We demonstrated that estrogen up-regulated the transcription of ATBF1, which was mediated by the direct binding of the ER onto the ATBF1 promoter, and that a half-estrogen-responsive element in the ATBF1 promoter was essential for ER direct binding. Furthermore, we found that estrogen at lower levels increased, but at higher levels decreased the expression of ATBF1 protein, which involved the degradation of ATBF1 protein by the estrogen-responsive proteasome system. ATBF1 protein levels fluctuate with estrogen levels. Although lower levels of estrogen increased ATBF1 protein expression, ATBF1 still inhibited cell proliferation caused by lower levels of estrogen. These findings not only reveal an autoregulatory feedback loop between ATBF1 and estrogen-ER signaling but also suggest that ATBF1 plays a role in both the maintenance of breast epithelial homeostasis and breast tumorigenesis caused by elevated estrogen levels.
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Estrogen increases the permeability of cultured human cervical epithelia (Gorodeski, GI. Am J Physiol Cell Physiol 275: C888–C899, 1998), and the effect is blocked by the estrogen receptor modulators ICI-182780 and tamoxifen. The objective of the study was to determine involvement of estrogen receptor(s) in mediating the effects on permeability. In cultured human cervical epithelial cells estradiol binds to high-affinity, low-capacity sites, in a specific and saturable manner. Scatchard analysis revealed a single class of binding sites with a dissociation constant of 1.3 nM and binding activity of ∼0.5 pmol/mg DNA. Estradiol increased the density of estrogen-binding sites in a time- and dose-related manner (half time ≈ 4 h, and EC 50 ≈ 1 nM). RT-PCR assays revealed the expression of mRNA for the estrogen receptor α (αER) and estrogen receptor β (βER). Removal of estrogen from the culture medium decreased and treatment with estrogen increased the expression of αER and βER mRNA. In cells not treated with estrogen, ICI-182780 and tamoxifen increased βER mRNA. In cells treated with estrogen, neither ICI-182780 nor tamoxifen had modulated significantly the increase in αER or βER mRNA. The transcription inhibitor actinomycin D blocked the estrogen-induced increase in permeability, and it abrogated the estradiol-induced increase in estrogen binding sites. These results suggest that the estrogen-dependent increase in cervical permeability is mediated by an αER-dependent increase in transcription.
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The present study aimed to evaluate the effect of OCT3/4 on the invasion and metastasis ability of gastric cancer. First, the expression level of OCT3/4 was detected in gastric cancer tissues of different tumor‑node‑metastasis stages. Furthermore, the correlation between the expression of OCT3/4 and the invasion ability of gastric cancer cells, and the probable regulatory mechanism were observed by RNA interference of OCT3/4 in gastric cancer cell strain MKN28, so as to provide the molecular mechanism for the occurrence and development of gastric cancer. The present study found the expression of OCT3/4 in gastric carcinoma tissues (22.56±8.72%) was markedly higher compared with that in para‑cancer tissue (1.12±0.18%) (P<0.01). The expression of OCT3/4 was associated with the infiltration degree, and demonstrated an increasing tendency from Tis‑T4 stages or from N0‑N3. The expression of OCT3/4 in M0 tissues was markedly lower than that in M1 tissues (P<0.01). The level of OCT3/4 was markedly decreased following transfection with OCT3/4 small interfering (si)RNA (P<0.01). The number of cell clones was reduced in a dose‑dependent manner following transfection with increasing levels of siRNA, and the number of cells that permeated through the filter membrane was also decreased. It may be concluded that the expression of OCT3/4 increases along with the degree of the infiltration and metastasis of gastric carcinoma, and that OCT3/4 siRNA inhibits the invasion of gastric carcinoma cells.
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The expression of microRNA-203 (miR-203) in esophageal squamous cell carcinoma (ESCC) tissues is remarkably lower than that in non‑ESCC tissues. We investigated how miR-203 could influence the development of ESCC cells. Our analyses revealed that miR-203 inhibited the migration and invasion of ESCC cells. Genome-wide gene expression data and target site inhibition assays showed that miR-203 appears to directly regulate LIM and SH3 protein 1 (LASP1). The knockdown of LASP1 resulted in inhibition of the migration and invasion of ESCC cells. Our results suggest that miR-203 and its target LASP1, may be associated with the progression of ESCC. In clinical ESCC specimens, the expression levels of miR-203, which were lower compared to those in normal tissues, were inversely correlated with the mRNA expression levels of LASP1. Moreover, we found that there was a significant correlation between the expression levels of miR-203 and the relapse‑free survival. The identification of a cancer network regulated by miR-203 could provide new insights into the potential mechanisms of the progression of ESCC.
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The definition of the role of estrogen is a long-date scientific preoccupation. On the basis of the studies carried out in the last twenty years, it is now well accepted that estradiol and its cognate receptors are relevant transcription regulators in reproductive as well as non-reproductive tissues. Models of estrogen (E2) insufficiency (ArKO) and estrogen receptors (ER) dysfunction (ERKOs) have revealed new and unexpected roles of estradiol and its receptors both in female and male. The purpose of this study is to use mouse models of estrogen insufficiency (ArKO) and estrogen receptors dysfunction (ERKOs) to provide a genomic insight in the multiple and complex mechanisms defining estrogenic signaling to help understanding its role in physiological and pathological conditions. In particular the objective was to identify the genes responsive to estrogen signaling according to various possible mechanisms: 1) estrogen and estrogen receptordependent actions; 2) estrogen-independent and estrogen-receptor-dependent actions; 3) estrogen receptor-independent estrogen-dependent actions. To reach this aim, estrogen and estrogen receptors dependent genes expression profiling were performed by microarray analysis in ventral and dorso-lateral prostate and gonadal white adipose tissue from mouse models of impaired estrogen synthesis (ArKO) and ER action (ERKOs). The experimental and biological reproducibility of microarray data was first verified and confirmed providing a correlation between real-time PCR and microarrays in fold change measurements and in expression profiles across all tissues. The results obtained from the analysis of the expression profiles indicate that the classical and the non-genomic actions of estrogen are not to represent the main mechanisms of estrogenic signaling in prostate and adipose tissue. Conversely it appears that the estrogenic signaling in these tissues is exerted via estrogen receptors with an estrogen-independent mechanism of action. ERa appear to be the main mediator of the observed estrogenic effects, with mechanisms that differ according to the specific tissue. In ventral and dorso-lateral prostates, ERa seems to have inhibitory effects on transcription of target genes, supporting the hypothesis of its implication as a tumor suppressor in the prostate gland. Additional studies need to be performed to permit the identification of genes whose regulation can be directly modulated by ERs.
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AIM:To investigate the expression of estrogen receptors in myocardium of ovariectomized female rats.METHODS:One week after bilateral ovariectomy,the female SD rats were divided into 3 groups randomly:OVX +estrogen(0.15 mg/kg,s.c.),OVX + normal sodium and control.After 4 weeks of treatment,the expression of estrogen receptors in the myocardium were evaluated by Western blotting.RESULTS:After ovariectomy,serum estrogen decreased significantly,compared with control[(88±22 vs 403±59)pmol/L,P0.05],the expression of estrogen receptors decreased(P0.05).After estrogen replacement therapy,serum estrogen increased[(3864±105)pmol/L],estrogen upregulated the expression of ERβ receptor(P0.05)and downregulated ERα receptor(P0.05)in myocardium.CONCLUSION:Estrogen replacement modifies the expression of estrogen receptors in myocardium of ovariectomized female rats.
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