The role of CyclinD1 and estrogen receptor (ER) in the process of proliferation and metastasis of breast neoplasm and their relationship were studied. The expression levels of CyclinD1 and ER in the tissue samples wer...The role of CyclinD1 and estrogen receptor (ER) in the process of proliferation and metastasis of breast neoplasm and their relationship were studied. The expression levels of CyclinD1 and ER in the tissue samples were detected by using flow cytometry and L SAB immunohistochemistry staining, respectively. The results showed that CyclinD1 and ER expression levels in breast cancer were significantly higher than in benign breast neoplasm (P<0.05). The CyclinD1 expression levels in stage I was much lower than in stages Ⅱ, Ⅲ, Ⅳ (P<0.05). The positive rate of ER was not related with tumor size, lymph node metastasis and TNM stage (P>0.05), but the CyclinD1 expression level in ER (+) group was significantly higher than in ER (-) group (P<0.05). It was concluded that CyclinD1 expression level might be obviously related with the proliferation and metastasis of breast neoplasm and ER.展开更多
Worldwide, gastric cancer is one of the most common malignancies with high mortality. Various aspects of thedevelopment and progression of gastric cancer continue to be extensively investigated in order to further our...Worldwide, gastric cancer is one of the most common malignancies with high mortality. Various aspects of thedevelopment and progression of gastric cancer continue to be extensively investigated in order to further our understanding and provide more effective means for the prevention, diagnosis, and treatment of the disease. Estrogen receptors(ERs) are steroid hormone receptors that regulate cellular activities in many physiological and pathological processes in different tissues. There are two distinct forms of ERs, namely ERα and ERβ, with several alternative-splicing isoforms for each. They show distinct tissue distribution patterns and exert different biological functions. Dysregulation of ERs has been found to be associated closely with many diseases, including cancer. A number of studies have been conducted to investigate the role of ERs in gastric cancer, the possible mechanisms underlying these roles, and the clinical relevance of deregulated ERs in gastric cancer patients. To date, inconsistent associations of different ERs with gastric cancer have been reported. These inconsistencies may be caused by variations in in vitro cell models and clinical samples, including assay conditions and protocols with regard to different forms of ERs. Given the potential of the deregulated ERs as diagnostic/prognostic markers or therapeutic targets for gastric cancer, it will be important to identify/confirm the association of each ER isoform with gastric cancer, to determine the specific roles and interactions that these individual ER isoforms play under specific conditions in the development and/or progression of gastric cancer, and to elucidate precisely these mechanisms. In this review, we summarize the achievements from early ER studies in gastric cancer to the most up-to-date discoveries, with an effort to provide a comprehensive understanding of the role of ERs roles in gastric cancer and its possible mechanisms. Furthermore, we propose directions for future investigations.展开更多
AIM: To investigate the prognostic significance of estrogen receptor 1(ER1) and vascular endothelial growth factor A(VEGF-A) expression in primary gallbladder carcinoma(GBC) to identify new prognostic markers for this...AIM: To investigate the prognostic significance of estrogen receptor 1(ER1) and vascular endothelial growth factor A(VEGF-A) expression in primary gallbladder carcinoma(GBC) to identify new prognostic markers for this malignancy.METHODS: Using immunohistochemistry, we investigated ER1 and VEGF-A expression in 78 GBC and 78 cholelithiasis(CS) tissues. The results were correlated with clinicopathological features. Univariate and multivariate analyses were performed to evaluate the relationship between ER1 and VEGF-A expression and patients' prognosis. Further Kaplan-Meier survival analysis was also performed. RESULTS: ER1 and VEGF-A expression was significantly higher in GBC compared with CS(47/78 vs 28/78, P < 0.05; 51/78 vs 33/78, P < 0.05). ER1 expression was correlated with gender(P < 0.05) and VEGF-A expression was correlated with tumor differentiation in GBC patients(P < 0.05). In univariate analysis, age and tumor node metastasis(TNM) stage were factors associated with GBC prognosis(P < 0.05). Although there was no statistical difference between the expression of ER1 or VEGF-A and overall survival, the high expression of ER1 combined with VEGF-A predicted a poor prognosis for GBC patients(16.30 ± 1.87 vs 24.97 ± 2.09, log-rank P < 0.05). In multivariate analysis, combined expression of ER1 and VEGF-A and TNM stage were independent prognostic factors for GBC patients(P < 0.05).CONCLUSION: Combined expression of ER1 and VEGF-A is a potential prognostic marker for GBC patients. Clinical detection of ER1 and VEGF-A in surgically resected GBC tissues would provide animportant reference for decision-making of postoperative treatment programs.展开更多
A protective role of the sex steroid hormone estrogenin hepatocellular carcinoma(HCC) was suggested a few decades ago according to clinical data showing higher HCC morbidity and mortality among males. Several recent s...A protective role of the sex steroid hormone estrogenin hepatocellular carcinoma(HCC) was suggested a few decades ago according to clinical data showing higher HCC morbidity and mortality among males. Several recent studies further confirmed the anti-cancer effects of estrogen in the liver. However, it remains to be identified how to exploit estrogen signalling within clinical settings for HCC treatment. There are several unresolved issues related to the estrogen pathway in liver cells. The main problems include the absence of a clear understanding of which estrogen receptor(ER) isoform is predominantly expressed in normal and malignant liver cells, the ER isoform expression difference between males and females, and which ER isoform should be targeted when designing HCC therapy. Some of those questions were recently addressed by Iyer and coauthors. The current editorial review critically analyses the study by Iyer et al(WJG, 2017) that investigated the expression of ER subtypes in liver samples collected from patients with a healthy liver, hepatitis C virus cirrhosis, and HCC. ER presence was evaluated in association with gender, intracellular localization, inflammation marker NF-kB, and proliferation-related effector cyclin D1. The study limitations and advantages are discussed in light of recent advances in the HCC and estrogen signalling areas.展开更多
AIM: To investigate the role of diarylpropionitrile(DPN), a selective agonist of estrogen receptor β(ERβ), in liver cirrhosis with portal hypertension(PHT) and isolated hepatic stellate cells(HSCs).METHODS: Female S...AIM: To investigate the role of diarylpropionitrile(DPN), a selective agonist of estrogen receptor β(ERβ), in liver cirrhosis with portal hypertension(PHT) and isolated hepatic stellate cells(HSCs).METHODS: Female Sprague-Dawley rats were ovariectomized(OVX), and liver cirrhosis with PHT was induced by CCl4 injection. DPN and PHTPP, the selective ERβ agonist and antagonist, were used as drug interventions. Liver fibrosis was assessed by hematoxylin and eosin(HE) and Masson's trichrome staining and by analyzing smooth muscle actin expression. Hemodynamic parameters were determined in vivo using colored microspheres technique. Protein expression and phosphorylation were determined by immunohistochemical staining and Western blot analysis. Messenger RNA levels were analyzed by quantitative real-time polymerase chain reaction(q RT-PCR). Collagengel contraction assay was performed using gel lattices containing HSCs treated with DPN, PHTPP, or Y-27632 prior to ET-1 addition. RESULTS: Treatment with DPN in vivo greatly lowered portal pressure and improved hemodynamic parameters without affecting mean arterial pressure, which was associated with the attenuation of liver fibrosis and intrahepatic vascular resistance(IHVR). In CCl4-treated rat livers, DPN significantly decreased the expression of Rho A and ROCK Ⅱ, and even suppressed ROCK Ⅱ activity. Moreover, DPN remarkedly increased the levels of endothelial nitric oxide synthase(e NOS) and phosphorylated e NOS, and promoted the activities of protein kinase G(PKG), which is an NO effector in the liver. Furthermore, DPN reduced the contractility of activated HSCs in the 3-dimensional stress-relaxed collagen lattices, and decreased the ROCK Ⅱ activity in activated HSCs. Finally, in vivo /in vitro experiments demonstrated that MLC activity was inhibited by DPN.CONCLUSION: For OVX rats with liver cirrhosis, DPN suppressed liver Rho A/ROCK signal, facilitated NO/PKG pathways, and decreased IHVR, giving rise to reduced portal pressure. Therefore, DPN represents a relevant treatment choice against PHT in cirrhotic patients, especially postmenopausal women.展开更多
Approximately 80% of breast cancers(BC) are estrogen receptor(ER)-positive and thus endocrine therapy(ET) should be considered complementary to surgery in the majority of patients. The advantages of oophorectomy, adre...Approximately 80% of breast cancers(BC) are estrogen receptor(ER)-positive and thus endocrine therapy(ET) should be considered complementary to surgery in the majority of patients. The advantages of oophorectomy, adrenalectomy and hypophysectomy in women with advanced BC have been demonstrated many years ago, and currently ET consist of(1) ovarian function suppression(OFS), usually obtained using gonadotropinreleasing hormone agonists(Gn RHa);(2) selective estrogen receptor modulators or down-regulators(SERMs or SERDs); and(3) aromatase inhibitors(AIs), or a combination of two or more drugs. For patients aged less than 50 years and ER+ BC, there is no conclusive evidence that the combination of OFS and SERMs(i.e., tamoxifen) or chemotherapy is superior to OFS alone. Tamoxifen users exhibit a reduced risk of BC, both invasive and in situ, especially during the first 5 years of therapy, and extending the treatment to 10 years further reduced the risk of recurrences. SERDs(i.e., fulvestrant) are especially useful in the neoadjuvant treatment of advanced BC, alone or in combination with either cytotoxic agents or AIs. There are two types of AIs: type Ⅰ are permanent steroidal inhibitors of aromatase, while type Ⅱ are reversible nonsteroidal inhibitors. Several studies demonstrated the superiority of the third-generation AIs(i.e., anastrozole and letrozole) compared with tamoxifen, and adjuvant therapy with AIs reduces the recurrence risk especially in patients with advanced BC. Unfortunately, some cancers are or became ET-resistant, and thus other drugs have been suggested in combination with SERMs or AIs, including cyclin-dependent kinase 4/6 inhibitors(palbociclib) and mammalian target of rapamycin(m TOR) inhibitors, such as everolimus. Further studies are required to confirm their real usefulness.展开更多
Objective: To investigate estrogen receptor β (ERβ) gene Rsa1 polymorphism and concentration of estrogen, FSH and LH in serum in peri-menopausal and menopausal women with depressive disorder. Methods: Seventy-four p...Objective: To investigate estrogen receptor β (ERβ) gene Rsa1 polymorphism and concentration of estrogen, FSH and LH in serum in peri-menopausal and menopausal women with depressive disorder. Methods: Seventy-four peri-menopausal and menopausal women with depressive disorder met ICD-10 and CCMD-3 assessment criteria for depressive disorder were recruited. ERβ gene Rsa1 polymorphism was analyzed with PCR-RFLP. Serum levels of estrogen, FSH and LH were measured by magnetism-ELISA. Results: The respective frequency of ERβ gene Rsa1 polymorphism was no significant difference between women with depressive disorder and the healthy women (χ 2=1.106,P>0.05). The serum level of estrogen was lower in women with depressive disorder than in the healthy women (P<0.05). No difference was found for FSH and LH between two groups. Conclusion: ERβ gene Rsa1 polymorphism may be not associated with depressive disorder in the peri-menopausal and menopausal women. The serum level of estrogen is associated with depressive disorder in the peri-menopausal and menopausal women.展开更多
BACKGROUND:Virological clearance,delayed progression to cirrhosis or liver cancer,and increased survival are the long-term goals of antiviral therapy in chronic hepatitis B patients.Identification of host factors corr...BACKGROUND:Virological clearance,delayed progression to cirrhosis or liver cancer,and increased survival are the long-term goals of antiviral therapy in chronic hepatitis B patients.Identification of host factors correlated with therapeutic response may contribute greatly to individual treatment.This study aimed at investigating whether T29C genotype polymorphism of estrogen receptor alpha(ESR1) is associated with the initial response to interferon-alpha(IFN-α)therapy in chronic hepatitis B patients.METHODS:The initial responses of 100 patients to IFN-α therapy were evaluated and compared by classifying them into three groups according to T29C genotype polymorphism of ESR1:T/T,T/C,and C/C genotype groups.Polymerase chain reaction-restriction fragment length polymorphism was used to analyze the genotype polymorphism in T29C.RESULTS:The frequency of initially combined response was markedly higher in both the T/T and T/C groups than in the C/C group(Z=10.326,P=0.006 and Z=26.247,P=0.000, respectively).In addition,the initial virological response was higher in the T/T and T/C groups than the C/C group(χ2=5.674, P=0.017 andχ2=4.980,P=0.026,respectively).In 78 initially HBeAg-positive patients,however,the frequency of initial e-antigen disappearance or seroconversion among the T/T,T/C, and C/C genotype groups was 34.15%,27.78%and 15.79%, respectively,which were not significantly different.CONCLUSION:The T29C genotype polymorphism of ESR1 is associated with the initial response to IFN-αin patients with chronic hepatitis B,and might be a significant marker for predicting the initial response to IFN-α,at least in this study population.展开更多
Although a wide range of studies have addressed the relationship between estrogen receptor(ER) expression and prognosis in non-small cell lung cancer(NSCLC), that relationship remains controversial. This is in large p...Although a wide range of studies have addressed the relationship between estrogen receptor(ER) expression and prognosis in non-small cell lung cancer(NSCLC), that relationship remains controversial. This is in large part because there is no consensus on the rate of ER expression in NSCLC or on the intracellular distribution of ER expression. This suggests that establishing the relationship between ER expression and prognosis will require standardization of the antibodies used as well as the definition of a positive response. For example, it is supposed from previous studies that ERs in the cytoplasm and nucleus have different relationships to prognosis than ERs in the cytoplasm. Moreover, ER signaling in NSCLC is known to be affected by aromatase, progesterone receptor and epidermal growth factor receptor mutation. However, there has been little functional analysis these mutants and subtypes. This review will focus on what is known about the role of ERs in NSCLC and whether ER can be a useful prognostic marker or therapeutic target in NSCLC.展开更多
Estrogen receptor alpha(ERα) is detected in more than 70% of the cases of breast cancer. Nuclear activity of ERα, a transcriptional regulator, is linked to the development of mammary tumors, whereas the extranuclear...Estrogen receptor alpha(ERα) is detected in more than 70% of the cases of breast cancer. Nuclear activity of ERα, a transcriptional regulator, is linked to the development of mammary tumors, whereas the extranuclear activity of ERα is related to endocrine therapy resistance. ERα polyubiquitination is induced by the estradiol hormone, and also by selective estrogen receptor degraders, resulting in ERα degradation via the ubiquitin proteasome system. Moreover, polyubiquitination is related to the ERα transcription cycle, and some E3-ubiquitin ligases also function as coactivators for ERα. Several studies have demonstrated that ERα polyubiquitination is inhibited by multiple mechanisms that include posttranslational modifica-tions, intera-ctions with coregula-tors, a-nd forma-tion of specific protein complexes with ERα. These events are responsible for an increase in ERα protein levels and deregulation of its signaling in breast cancers. Thus, ERα polyubiquitination inhibition may be a key factor in the progression of breast cancer and resistance to endocrine therapy.展开更多
Twenty-five years ago,Nembrot and colleagues reported amplification of the estrogen receptor alpha gene(ESR1) in breast cancer,initiating a broad and still ongoing scientific debate on the prevalence and clinical sign...Twenty-five years ago,Nembrot and colleagues reported amplification of the estrogen receptor alpha gene(ESR1) in breast cancer,initiating a broad and still ongoing scientific debate on the prevalence and clinical significance of this genetic aberration,which affects one of the most important genes in breast cancer.Since then,a multitude of studies on this topic has been published,covering a wide range of divergent results and arguments.The reported prevalence of this alteration in breast cancer ranges from 0% to 75%,suggesting that ESR1 copy number analysis is hampered by technical and interpreter issues.To date,two major issues related to ESR1 amplification remain to be conclusively addressed:(1) The extent to which abundant amounts of messenger RNA can mimic amplification in standard fluorescence in situ hybridization assays in the analysis of strongly expressed genes like ESR1,and(2) the clinical relevance of ESR1 amplification:Such relevance is strongly disputed,with data showing predictive value for response as well as for resistance of the cancer to anti-estrogen therapies,or for subsequent development of cancers in the case of precursor lesions that display amplification of ESR1.This review provides a comprehensive summary of the various views on ESR1 amplification,and highlights explanations for the contradictions and conflicting data that could inform future ESR1 research.展开更多
To evaluate the effect of GnRHa induced superovulation protocol on endometrial morphology and function. Material & Methods Forty ICR mice were randomly allocated into 4 groups, among them, 2 experimental groups we...To evaluate the effect of GnRHa induced superovulation protocol on endometrial morphology and function. Material & Methods Forty ICR mice were randomly allocated into 4 groups, among them, 2 experimental groups were injected with GnRHa+HMG+hCG, another 2 groups were given saline of same volume as control group. The uterine tissues were investigated at 24 h and 48 h after administration (experimental group) or ovulation (control group).The endometrial thickness, the size of gland and glandular lumen, the total area of glandular cells, the average height of glandular epithelium were measured from routine histological slides using computerized image analysis. The SP immunohistochemistry techniques with monoclonal antibodies were employed to semi quantitatively analize the estrogen receptor (ER) and progesterone receptor (PR) in glandular cells. Results The endometrial thickness was not significantly different between experimental groups and control groups at 24 h and 48 h (P>0.05).The average area, perimeter, maximal diameter of single gland and glandular lumen, the total area, average height of glandular epithelium in experimental groups were significantly smaller than those of in control groups at equivalent time stages (all P<0.01). The asynchronous development of gland epithelium and stroma cells, namely, pesudostratified glandular epithelium and predecidual changes of stroma cells were seen at same time in experimental groups. The positive percentage (%) and expression intense of ER and PR in glandular epithelium cells were significantly lower in experimental groups than in control groups (P<0.05). Conclusion The protocol with GnRHa had a negative effect on endometrial histological structure and down regulated the express of ER and PR, suggesting that this protocol effect on the endometrial morphology and function and could not facilitate the formation of a physiologic endometrium completely, which may be one of the causes of low pregnancy rates.展开更多
Background: Voltage-gated sodium channel 1.5(Nav1.5) potentially promotes the migratory and invasive behaviors of colon cancer cells. Hitherto, the prognostic significance of Nav1.5 expression remains undetermined. Th...Background: Voltage-gated sodium channel 1.5(Nav1.5) potentially promotes the migratory and invasive behaviors of colon cancer cells. Hitherto, the prognostic significance of Nav1.5 expression remains undetermined. The present study aimed to explore the associations of Nav1.5 expression with clinical outcomes and estrogen receptor-β(ER-β)expression in non-metastatic colon cancer patients receiving radical resection.Methods: A total of 269 consecutive patients with pathologically confirmed stages Ⅰ-Ⅲ colon cancer who underwent radical resection were selected. Nav1.5 and ER-β expression was detected by using immunohistochemistry(IHC)on tissue microarray constructed from paraffin-embedded specimens. IHC score was determined according to the percentage and intensity of positively stained cells. Statistical analysis was performed with the X-tile method, k coefficient, Chi square test or Fisher's exact test, logistic regression, log-rank test, and Cox proportional hazards models.Results: We found that Nav1.5 was commonly expressed in tumor tissues with higher mean IHC score as compared with matched tumor-adjacent normal tissues(5.1 ± 3.5 vs. 3.5 ± 2.7, P < 0.001).The high expression of Nav1.5 in colon cancer tissues was associated with high preoperative carcinoembryonic antigen level [odds ratio(OR) = 2.980;95% confidential interval(CI)1.163-7.632; P = 0.023] and high ER-β expression(OR = 2.808; 95% CI 1.243-6.343;p = 0.00 3). Log-rank test results showed that high Nav1.5 expression contributed to a low 5-year disease-free survival(DFS) rate in colon cancer patients(77.2% vs. 92.1%, P = 0.048), especially in patients with high ER-β expression tumor(76.2% vs. 91.3%, P = 0.032). Analysis with Cox proportional hazards model demonstrated that high Nav1.5 expression[hazard ratio(HR) = 2.738; 95% CI 1.100-6.819;P = 0.030] and lymph node metastasis(HR = 2.633; 95% CI 1.632-4.248; P < 0.001) were prognostic factors for unfavorable DFS in colon cancer patients.Conclusions: High expression of Nav1.5 was associated with high expression of ER-β and indicated unfavorable oncologic prognosis in patients with non-metastatic colon cancer.展开更多
to investigate the estrogen receptor(ER) expression in cartilage cell in the development of osteoarthritis induced by bilateral ovariectomy in guinea pig and to find their relationship. 30 two-month-old female guinea ...to investigate the estrogen receptor(ER) expression in cartilage cell in the development of osteoarthritis induced by bilateral ovariectomy in guinea pig and to find their relationship. 30 two-month-old female guinea pigs were randomly divided into two groups (n=15 each): sham operation (control )group and ovariectomized group (OVX); Scanning electorne microscope (SEM) and transmission electron microscope (TEM) were obtained to analysis the cartilage degeneration of the hind limb knee joint after 6 and 12 weeks of ovariectomy. Dextran-Coated-Charcoal (DCC) was taken to quantitively detect the expression of ER. The serum levels of estrogen and gestone were detected by immune contest assay. The results showed that ER do exist in the cartilages of the guinea pigs, with higher expression in the control group than in OVX group at the same time point (P<0.05). It was increased also at 12 th week after operation than that of preoperation. The blood serum levels of estrogen and gestone showed a similar tendency to the expression of ER. Joint cartilage degeneration detected by SEM and TEM could be found at 6 th week,but severe degenerative lesions at 12 th week in the OVX group compared with the control group (P<0.01). The data suggested that bilateral ovariectomy in guinea pig lead to severe osteoarthritis which mighgt be related to the lower serum level of estrogen and the downregulation of the expression of ER in the cartilage also.展开更多
Objective:To explore the mechanism of the estrogen-like effect of genistein by observing the expression of Matrix metalloproteinases-26(MMP-26)and ERa in human endometrial cancer cells(Ishikawa and HEC-1B)in vitro.Met...Objective:To explore the mechanism of the estrogen-like effect of genistein by observing the expression of Matrix metalloproteinases-26(MMP-26)and ERa in human endometrial cancer cells(Ishikawa and HEC-1B)in vitro.Methods:The effect of genistein on MMP-26 and ERa expression was examined by western blot in cultured Ishikawa and HEC-1B cells.Additionally,the effects of genistein on ERa-ERE-luc and ERb-ERE-luc reporter gene expression in HEC-1B cells were analyzed by luciferase activity assays.Results:MMP-26 and ERa protein expression was down-regulated by genistein treatment in Ishikawa cell induced by high concentration E2,whereas MMP-26 and ERa protein expression was up-regulated by genistein treatment in Ishikawa cells induced by low concentration E2.Expression of the ERa-ERE-luc and ERb-ERE-luc reporter genes was significantly increased after E2 induction and was further up-regulated by genistein.Expression of ERa-ERE-luc and ERb-ERE-luc reporter genes decreased significantly following genistein treatment in high E2 concentrations,and increased significantly following genistein treatment in low E2 concentrations.Conclusions:Genistein showed estrogen-like effects in endometrial cancer cells and influenced estrogen receptor signaling by modulating ERa and ERb expression.展开更多
Estrogen plays an important role in regulating Sertoli cell number in the testis.The objective of the study was to identify whether 17β-estradiol affected the proliferation of cultured,immature boar Sertoli cells via...Estrogen plays an important role in regulating Sertoli cell number in the testis.The objective of the study was to identify whether 17β-estradiol affected the proliferation of cultured,immature boar Sertoli cells via the estrogen receptor β(ERβ) and the cAMP-extracellular signal-regulated kinase(ERK1/2) pathway.Low levels(10-10-10-8 mol L-1) of 17β-estradiol increased cell number,but high levels(10-7-10-6 mol L-1) decreased it(P < 0.05).Sertoli cell number began to recover for an additional 24 h in the medium without 17β-estradiol(10-6 mol L-1)(P > 0.05).The effects of 17β-estradiol(10-9 mol L-1) peaked at the first 24 h(P < 0.05).17β-estradiol activated ERK1/2 from 5 min to 24 h,but the activiy of ERK1/2 began to decrease after 4 h.Both PD98059 and U0126,two ERK inhibitors,blocked cell division(P < 0.05).17β-estradiol(10-10-10-6 mol L-1) dose-dependently increased cAMP production(P < 0.05),and both 17β-estradiol(10-9 mol L-1) and forskolin,which increases cAMP levels,induced cell proliferation and activated ERK1/2(P < 0.05).Rp-cAMP,an antagonist of cAMP,blocked this 17β-estradiol activity(P < 0.05).Two estrogen receptor antagonists,ICI 182780 and ERβ antagonist(ERβAnt),reduced Sertoli cell number,cAMP production and ERK1/2 activation(P < 0.05),but ERαAnt did not(P > 0.05).Therefore,17βestradiol mainly promotes pig Sertoli cell proliferation via ERβ to induce cAMP production and ERK activation to promote cell proliferation.展开更多
文摘The role of CyclinD1 and estrogen receptor (ER) in the process of proliferation and metastasis of breast neoplasm and their relationship were studied. The expression levels of CyclinD1 and ER in the tissue samples were detected by using flow cytometry and L SAB immunohistochemistry staining, respectively. The results showed that CyclinD1 and ER expression levels in breast cancer were significantly higher than in benign breast neoplasm (P<0.05). The CyclinD1 expression levels in stage I was much lower than in stages Ⅱ, Ⅲ, Ⅳ (P<0.05). The positive rate of ER was not related with tumor size, lymph node metastasis and TNM stage (P>0.05), but the CyclinD1 expression level in ER (+) group was significantly higher than in ER (-) group (P<0.05). It was concluded that CyclinD1 expression level might be obviously related with the proliferation and metastasis of breast neoplasm and ER.
基金Supported by The National Natural Science Foundation of ChinaNo.30271450+1 种基金No.30471955No.30672365 and No.81172516
文摘Worldwide, gastric cancer is one of the most common malignancies with high mortality. Various aspects of thedevelopment and progression of gastric cancer continue to be extensively investigated in order to further our understanding and provide more effective means for the prevention, diagnosis, and treatment of the disease. Estrogen receptors(ERs) are steroid hormone receptors that regulate cellular activities in many physiological and pathological processes in different tissues. There are two distinct forms of ERs, namely ERα and ERβ, with several alternative-splicing isoforms for each. They show distinct tissue distribution patterns and exert different biological functions. Dysregulation of ERs has been found to be associated closely with many diseases, including cancer. A number of studies have been conducted to investigate the role of ERs in gastric cancer, the possible mechanisms underlying these roles, and the clinical relevance of deregulated ERs in gastric cancer patients. To date, inconsistent associations of different ERs with gastric cancer have been reported. These inconsistencies may be caused by variations in in vitro cell models and clinical samples, including assay conditions and protocols with regard to different forms of ERs. Given the potential of the deregulated ERs as diagnostic/prognostic markers or therapeutic targets for gastric cancer, it will be important to identify/confirm the association of each ER isoform with gastric cancer, to determine the specific roles and interactions that these individual ER isoforms play under specific conditions in the development and/or progression of gastric cancer, and to elucidate precisely these mechanisms. In this review, we summarize the achievements from early ER studies in gastric cancer to the most up-to-date discoveries, with an effort to provide a comprehensive understanding of the role of ERs roles in gastric cancer and its possible mechanisms. Furthermore, we propose directions for future investigations.
基金Supported by National Natural Science Foundation of China,No.81272644 and No.81201549
文摘AIM: To investigate the prognostic significance of estrogen receptor 1(ER1) and vascular endothelial growth factor A(VEGF-A) expression in primary gallbladder carcinoma(GBC) to identify new prognostic markers for this malignancy.METHODS: Using immunohistochemistry, we investigated ER1 and VEGF-A expression in 78 GBC and 78 cholelithiasis(CS) tissues. The results were correlated with clinicopathological features. Univariate and multivariate analyses were performed to evaluate the relationship between ER1 and VEGF-A expression and patients' prognosis. Further Kaplan-Meier survival analysis was also performed. RESULTS: ER1 and VEGF-A expression was significantly higher in GBC compared with CS(47/78 vs 28/78, P < 0.05; 51/78 vs 33/78, P < 0.05). ER1 expression was correlated with gender(P < 0.05) and VEGF-A expression was correlated with tumor differentiation in GBC patients(P < 0.05). In univariate analysis, age and tumor node metastasis(TNM) stage were factors associated with GBC prognosis(P < 0.05). Although there was no statistical difference between the expression of ER1 or VEGF-A and overall survival, the high expression of ER1 combined with VEGF-A predicted a poor prognosis for GBC patients(16.30 ± 1.87 vs 24.97 ± 2.09, log-rank P < 0.05). In multivariate analysis, combined expression of ER1 and VEGF-A and TNM stage were independent prognostic factors for GBC patients(P < 0.05).CONCLUSION: Combined expression of ER1 and VEGF-A is a potential prognostic marker for GBC patients. Clinical detection of ER1 and VEGF-A in surgically resected GBC tissues would provide animportant reference for decision-making of postoperative treatment programs.
文摘A protective role of the sex steroid hormone estrogenin hepatocellular carcinoma(HCC) was suggested a few decades ago according to clinical data showing higher HCC morbidity and mortality among males. Several recent studies further confirmed the anti-cancer effects of estrogen in the liver. However, it remains to be identified how to exploit estrogen signalling within clinical settings for HCC treatment. There are several unresolved issues related to the estrogen pathway in liver cells. The main problems include the absence of a clear understanding of which estrogen receptor(ER) isoform is predominantly expressed in normal and malignant liver cells, the ER isoform expression difference between males and females, and which ER isoform should be targeted when designing HCC therapy. Some of those questions were recently addressed by Iyer and coauthors. The current editorial review critically analyses the study by Iyer et al(WJG, 2017) that investigated the expression of ER subtypes in liver samples collected from patients with a healthy liver, hepatitis C virus cirrhosis, and HCC. ER presence was evaluated in association with gender, intracellular localization, inflammation marker NF-kB, and proliferation-related effector cyclin D1. The study limitations and advantages are discussed in light of recent advances in the HCC and estrogen signalling areas.
基金Supported by the National Natural Science Foundation for the Youth of China,No.81400630
文摘AIM: To investigate the role of diarylpropionitrile(DPN), a selective agonist of estrogen receptor β(ERβ), in liver cirrhosis with portal hypertension(PHT) and isolated hepatic stellate cells(HSCs).METHODS: Female Sprague-Dawley rats were ovariectomized(OVX), and liver cirrhosis with PHT was induced by CCl4 injection. DPN and PHTPP, the selective ERβ agonist and antagonist, were used as drug interventions. Liver fibrosis was assessed by hematoxylin and eosin(HE) and Masson's trichrome staining and by analyzing smooth muscle actin expression. Hemodynamic parameters were determined in vivo using colored microspheres technique. Protein expression and phosphorylation were determined by immunohistochemical staining and Western blot analysis. Messenger RNA levels were analyzed by quantitative real-time polymerase chain reaction(q RT-PCR). Collagengel contraction assay was performed using gel lattices containing HSCs treated with DPN, PHTPP, or Y-27632 prior to ET-1 addition. RESULTS: Treatment with DPN in vivo greatly lowered portal pressure and improved hemodynamic parameters without affecting mean arterial pressure, which was associated with the attenuation of liver fibrosis and intrahepatic vascular resistance(IHVR). In CCl4-treated rat livers, DPN significantly decreased the expression of Rho A and ROCK Ⅱ, and even suppressed ROCK Ⅱ activity. Moreover, DPN remarkedly increased the levels of endothelial nitric oxide synthase(e NOS) and phosphorylated e NOS, and promoted the activities of protein kinase G(PKG), which is an NO effector in the liver. Furthermore, DPN reduced the contractility of activated HSCs in the 3-dimensional stress-relaxed collagen lattices, and decreased the ROCK Ⅱ activity in activated HSCs. Finally, in vivo /in vitro experiments demonstrated that MLC activity was inhibited by DPN.CONCLUSION: For OVX rats with liver cirrhosis, DPN suppressed liver Rho A/ROCK signal, facilitated NO/PKG pathways, and decreased IHVR, giving rise to reduced portal pressure. Therefore, DPN represents a relevant treatment choice against PHT in cirrhotic patients, especially postmenopausal women.
文摘Approximately 80% of breast cancers(BC) are estrogen receptor(ER)-positive and thus endocrine therapy(ET) should be considered complementary to surgery in the majority of patients. The advantages of oophorectomy, adrenalectomy and hypophysectomy in women with advanced BC have been demonstrated many years ago, and currently ET consist of(1) ovarian function suppression(OFS), usually obtained using gonadotropinreleasing hormone agonists(Gn RHa);(2) selective estrogen receptor modulators or down-regulators(SERMs or SERDs); and(3) aromatase inhibitors(AIs), or a combination of two or more drugs. For patients aged less than 50 years and ER+ BC, there is no conclusive evidence that the combination of OFS and SERMs(i.e., tamoxifen) or chemotherapy is superior to OFS alone. Tamoxifen users exhibit a reduced risk of BC, both invasive and in situ, especially during the first 5 years of therapy, and extending the treatment to 10 years further reduced the risk of recurrences. SERDs(i.e., fulvestrant) are especially useful in the neoadjuvant treatment of advanced BC, alone or in combination with either cytotoxic agents or AIs. There are two types of AIs: type Ⅰ are permanent steroidal inhibitors of aromatase, while type Ⅱ are reversible nonsteroidal inhibitors. Several studies demonstrated the superiority of the third-generation AIs(i.e., anastrozole and letrozole) compared with tamoxifen, and adjuvant therapy with AIs reduces the recurrence risk especially in patients with advanced BC. Unfortunately, some cancers are or became ET-resistant, and thus other drugs have been suggested in combination with SERMs or AIs, including cyclin-dependent kinase 4/6 inhibitors(palbociclib) and mammalian target of rapamycin(m TOR) inhibitors, such as everolimus. Further studies are required to confirm their real usefulness.
文摘Objective: To investigate estrogen receptor β (ERβ) gene Rsa1 polymorphism and concentration of estrogen, FSH and LH in serum in peri-menopausal and menopausal women with depressive disorder. Methods: Seventy-four peri-menopausal and menopausal women with depressive disorder met ICD-10 and CCMD-3 assessment criteria for depressive disorder were recruited. ERβ gene Rsa1 polymorphism was analyzed with PCR-RFLP. Serum levels of estrogen, FSH and LH were measured by magnetism-ELISA. Results: The respective frequency of ERβ gene Rsa1 polymorphism was no significant difference between women with depressive disorder and the healthy women (χ 2=1.106,P>0.05). The serum level of estrogen was lower in women with depressive disorder than in the healthy women (P<0.05). No difference was found for FSH and LH between two groups. Conclusion: ERβ gene Rsa1 polymorphism may be not associated with depressive disorder in the peri-menopausal and menopausal women. The serum level of estrogen is associated with depressive disorder in the peri-menopausal and menopausal women.
基金supported by grants from the National Natural Science Foundation of China(No.30771907)the Foundation of Pre-973 Program Projects(No.2009CB526411)
文摘BACKGROUND:Virological clearance,delayed progression to cirrhosis or liver cancer,and increased survival are the long-term goals of antiviral therapy in chronic hepatitis B patients.Identification of host factors correlated with therapeutic response may contribute greatly to individual treatment.This study aimed at investigating whether T29C genotype polymorphism of estrogen receptor alpha(ESR1) is associated with the initial response to interferon-alpha(IFN-α)therapy in chronic hepatitis B patients.METHODS:The initial responses of 100 patients to IFN-α therapy were evaluated and compared by classifying them into three groups according to T29C genotype polymorphism of ESR1:T/T,T/C,and C/C genotype groups.Polymerase chain reaction-restriction fragment length polymorphism was used to analyze the genotype polymorphism in T29C.RESULTS:The frequency of initially combined response was markedly higher in both the T/T and T/C groups than in the C/C group(Z=10.326,P=0.006 and Z=26.247,P=0.000, respectively).In addition,the initial virological response was higher in the T/T and T/C groups than the C/C group(χ2=5.674, P=0.017 andχ2=4.980,P=0.026,respectively).In 78 initially HBeAg-positive patients,however,the frequency of initial e-antigen disappearance or seroconversion among the T/T,T/C, and C/C genotype groups was 34.15%,27.78%and 15.79%, respectively,which were not significantly different.CONCLUSION:The T29C genotype polymorphism of ESR1 is associated with the initial response to IFN-αin patients with chronic hepatitis B,and might be a significant marker for predicting the initial response to IFN-α,at least in this study population.
文摘Although a wide range of studies have addressed the relationship between estrogen receptor(ER) expression and prognosis in non-small cell lung cancer(NSCLC), that relationship remains controversial. This is in large part because there is no consensus on the rate of ER expression in NSCLC or on the intracellular distribution of ER expression. This suggests that establishing the relationship between ER expression and prognosis will require standardization of the antibodies used as well as the definition of a positive response. For example, it is supposed from previous studies that ERs in the cytoplasm and nucleus have different relationships to prognosis than ERs in the cytoplasm. Moreover, ER signaling in NSCLC is known to be affected by aromatase, progesterone receptor and epidermal growth factor receptor mutation. However, there has been little functional analysis these mutants and subtypes. This review will focus on what is known about the role of ERs in NSCLC and whether ER can be a useful prognostic marker or therapeutic target in NSCLC.
基金Supported by the DGAPA-UNAM,Nos.PAPIIT–IA200916 and PAPIIT–IA201618
文摘Estrogen receptor alpha(ERα) is detected in more than 70% of the cases of breast cancer. Nuclear activity of ERα, a transcriptional regulator, is linked to the development of mammary tumors, whereas the extranuclear activity of ERα is related to endocrine therapy resistance. ERα polyubiquitination is induced by the estradiol hormone, and also by selective estrogen receptor degraders, resulting in ERα degradation via the ubiquitin proteasome system. Moreover, polyubiquitination is related to the ERα transcription cycle, and some E3-ubiquitin ligases also function as coactivators for ERα. Several studies have demonstrated that ERα polyubiquitination is inhibited by multiple mechanisms that include posttranslational modifica-tions, intera-ctions with coregula-tors, a-nd forma-tion of specific protein complexes with ERα. These events are responsible for an increase in ERα protein levels and deregulation of its signaling in breast cancers. Thus, ERα polyubiquitination inhibition may be a key factor in the progression of breast cancer and resistance to endocrine therapy.
文摘Twenty-five years ago,Nembrot and colleagues reported amplification of the estrogen receptor alpha gene(ESR1) in breast cancer,initiating a broad and still ongoing scientific debate on the prevalence and clinical significance of this genetic aberration,which affects one of the most important genes in breast cancer.Since then,a multitude of studies on this topic has been published,covering a wide range of divergent results and arguments.The reported prevalence of this alteration in breast cancer ranges from 0% to 75%,suggesting that ESR1 copy number analysis is hampered by technical and interpreter issues.To date,two major issues related to ESR1 amplification remain to be conclusively addressed:(1) The extent to which abundant amounts of messenger RNA can mimic amplification in standard fluorescence in situ hybridization assays in the analysis of strongly expressed genes like ESR1,and(2) the clinical relevance of ESR1 amplification:Such relevance is strongly disputed,with data showing predictive value for response as well as for resistance of the cancer to anti-estrogen therapies,or for subsequent development of cancers in the case of precursor lesions that display amplification of ESR1.This review provides a comprehensive summary of the various views on ESR1 amplification,and highlights explanations for the contradictions and conflicting data that could inform future ESR1 research.
文摘To evaluate the effect of GnRHa induced superovulation protocol on endometrial morphology and function. Material & Methods Forty ICR mice were randomly allocated into 4 groups, among them, 2 experimental groups were injected with GnRHa+HMG+hCG, another 2 groups were given saline of same volume as control group. The uterine tissues were investigated at 24 h and 48 h after administration (experimental group) or ovulation (control group).The endometrial thickness, the size of gland and glandular lumen, the total area of glandular cells, the average height of glandular epithelium were measured from routine histological slides using computerized image analysis. The SP immunohistochemistry techniques with monoclonal antibodies were employed to semi quantitatively analize the estrogen receptor (ER) and progesterone receptor (PR) in glandular cells. Results The endometrial thickness was not significantly different between experimental groups and control groups at 24 h and 48 h (P>0.05).The average area, perimeter, maximal diameter of single gland and glandular lumen, the total area, average height of glandular epithelium in experimental groups were significantly smaller than those of in control groups at equivalent time stages (all P<0.01). The asynchronous development of gland epithelium and stroma cells, namely, pesudostratified glandular epithelium and predecidual changes of stroma cells were seen at same time in experimental groups. The positive percentage (%) and expression intense of ER and PR in glandular epithelium cells were significantly lower in experimental groups than in control groups (P<0.05). Conclusion The protocol with GnRHa had a negative effect on endometrial histological structure and down regulated the express of ER and PR, suggesting that this protocol effect on the endometrial morphology and function and could not facilitate the formation of a physiologic endometrium completely, which may be one of the causes of low pregnancy rates.
基金supported by a grant from the Sun Yat-sen University Clinical Research 5010 Program(Grant No.2015024)a grant of Guangzhou Science and Technology Plan Projects(Health Medical Collaborative Innovation Program of Guangzhou)(Grant No.201400000001-4)a grant of National Natural Science Foundation of China(Grant No.81772595)
文摘Background: Voltage-gated sodium channel 1.5(Nav1.5) potentially promotes the migratory and invasive behaviors of colon cancer cells. Hitherto, the prognostic significance of Nav1.5 expression remains undetermined. The present study aimed to explore the associations of Nav1.5 expression with clinical outcomes and estrogen receptor-β(ER-β)expression in non-metastatic colon cancer patients receiving radical resection.Methods: A total of 269 consecutive patients with pathologically confirmed stages Ⅰ-Ⅲ colon cancer who underwent radical resection were selected. Nav1.5 and ER-β expression was detected by using immunohistochemistry(IHC)on tissue microarray constructed from paraffin-embedded specimens. IHC score was determined according to the percentage and intensity of positively stained cells. Statistical analysis was performed with the X-tile method, k coefficient, Chi square test or Fisher's exact test, logistic regression, log-rank test, and Cox proportional hazards models.Results: We found that Nav1.5 was commonly expressed in tumor tissues with higher mean IHC score as compared with matched tumor-adjacent normal tissues(5.1 ± 3.5 vs. 3.5 ± 2.7, P < 0.001).The high expression of Nav1.5 in colon cancer tissues was associated with high preoperative carcinoembryonic antigen level [odds ratio(OR) = 2.980;95% confidential interval(CI)1.163-7.632; P = 0.023] and high ER-β expression(OR = 2.808; 95% CI 1.243-6.343;p = 0.00 3). Log-rank test results showed that high Nav1.5 expression contributed to a low 5-year disease-free survival(DFS) rate in colon cancer patients(77.2% vs. 92.1%, P = 0.048), especially in patients with high ER-β expression tumor(76.2% vs. 91.3%, P = 0.032). Analysis with Cox proportional hazards model demonstrated that high Nav1.5 expression[hazard ratio(HR) = 2.738; 95% CI 1.100-6.819;P = 0.030] and lymph node metastasis(HR = 2.633; 95% CI 1.632-4.248; P < 0.001) were prognostic factors for unfavorable DFS in colon cancer patients.Conclusions: High expression of Nav1.5 was associated with high expression of ER-β and indicated unfavorable oncologic prognosis in patients with non-metastatic colon cancer.
文摘to investigate the estrogen receptor(ER) expression in cartilage cell in the development of osteoarthritis induced by bilateral ovariectomy in guinea pig and to find their relationship. 30 two-month-old female guinea pigs were randomly divided into two groups (n=15 each): sham operation (control )group and ovariectomized group (OVX); Scanning electorne microscope (SEM) and transmission electron microscope (TEM) were obtained to analysis the cartilage degeneration of the hind limb knee joint after 6 and 12 weeks of ovariectomy. Dextran-Coated-Charcoal (DCC) was taken to quantitively detect the expression of ER. The serum levels of estrogen and gestone were detected by immune contest assay. The results showed that ER do exist in the cartilages of the guinea pigs, with higher expression in the control group than in OVX group at the same time point (P<0.05). It was increased also at 12 th week after operation than that of preoperation. The blood serum levels of estrogen and gestone showed a similar tendency to the expression of ER. Joint cartilage degeneration detected by SEM and TEM could be found at 6 th week,but severe degenerative lesions at 12 th week in the OVX group compared with the control group (P<0.01). The data suggested that bilateral ovariectomy in guinea pig lead to severe osteoarthritis which mighgt be related to the lower serum level of estrogen and the downregulation of the expression of ER in the cartilage also.
基金by National Nature Funds(No.30510403202)National Ministry of Education(No.IRT0413)Doctor Funds supported by National Ministry of Education(No.20050026012 and 20060026019).
文摘Objective:To explore the mechanism of the estrogen-like effect of genistein by observing the expression of Matrix metalloproteinases-26(MMP-26)and ERa in human endometrial cancer cells(Ishikawa and HEC-1B)in vitro.Methods:The effect of genistein on MMP-26 and ERa expression was examined by western blot in cultured Ishikawa and HEC-1B cells.Additionally,the effects of genistein on ERa-ERE-luc and ERb-ERE-luc reporter gene expression in HEC-1B cells were analyzed by luciferase activity assays.Results:MMP-26 and ERa protein expression was down-regulated by genistein treatment in Ishikawa cell induced by high concentration E2,whereas MMP-26 and ERa protein expression was up-regulated by genistein treatment in Ishikawa cells induced by low concentration E2.Expression of the ERa-ERE-luc and ERb-ERE-luc reporter genes was significantly increased after E2 induction and was further up-regulated by genistein.Expression of ERa-ERE-luc and ERb-ERE-luc reporter genes decreased significantly following genistein treatment in high E2 concentrations,and increased significantly following genistein treatment in low E2 concentrations.Conclusions:Genistein showed estrogen-like effects in endometrial cancer cells and influenced estrogen receptor signaling by modulating ERa and ERb expression.
基金supported by the National Natural Science Foundation of China(30270955)the Foundamental Research Funds for the Central Universities,China(XDJK2009B035)
文摘Estrogen plays an important role in regulating Sertoli cell number in the testis.The objective of the study was to identify whether 17β-estradiol affected the proliferation of cultured,immature boar Sertoli cells via the estrogen receptor β(ERβ) and the cAMP-extracellular signal-regulated kinase(ERK1/2) pathway.Low levels(10-10-10-8 mol L-1) of 17β-estradiol increased cell number,but high levels(10-7-10-6 mol L-1) decreased it(P < 0.05).Sertoli cell number began to recover for an additional 24 h in the medium without 17β-estradiol(10-6 mol L-1)(P > 0.05).The effects of 17β-estradiol(10-9 mol L-1) peaked at the first 24 h(P < 0.05).17β-estradiol activated ERK1/2 from 5 min to 24 h,but the activiy of ERK1/2 began to decrease after 4 h.Both PD98059 and U0126,two ERK inhibitors,blocked cell division(P < 0.05).17β-estradiol(10-10-10-6 mol L-1) dose-dependently increased cAMP production(P < 0.05),and both 17β-estradiol(10-9 mol L-1) and forskolin,which increases cAMP levels,induced cell proliferation and activated ERK1/2(P < 0.05).Rp-cAMP,an antagonist of cAMP,blocked this 17β-estradiol activity(P < 0.05).Two estrogen receptor antagonists,ICI 182780 and ERβ antagonist(ERβAnt),reduced Sertoli cell number,cAMP production and ERK1/2 activation(P < 0.05),but ERαAnt did not(P > 0.05).Therefore,17βestradiol mainly promotes pig Sertoli cell proliferation via ERβ to induce cAMP production and ERK activation to promote cell proliferation.