17β-Estradiol,through activating the G protein-coupled estrogen receptor,exacerbates the complication of benign prostatic hyperplasia in type 2 diabetes mellitus patients by inducing prostate proliferation

Benign prostatic hyperplasia(BPH)is one of the major chronic complications of type 2 diabetes mellitus(T2DM),and sex steroid hormones are common risk factors for the occurrence of T2DM and BPH.The profiles of sex steroid hormones are simultaneously quantified by LC-MS/MS in the clinical serum of patients,including simple BPH patients,newly diagnosed T2DM patients,T2DM complicated with BPH patients and matched healthy individuals.The G protein-coupled estrogen receptor(GPER)inhibitor G15,GPER knockdown lentivirus,the YAP1 inhibitor verteporfin,YAP1 knockdown/overexpression lentivirus,targeted metabolomics analysis,and Co-IP assays are used to investigate the molecular mechanisms of the disrupted sex steroid hormones homeostasis in the pathological process of T2DM complicated with BPH.The homeostasis of sex steroid hormone is disrupted in the serum of patients,accompanying with the proliferated prostatic epithelial cells(PECs).The sex steroid hormone metabolic profiles of T2DM patients complicated with BPH have the greatest degrees of separation from those of healthy individuals.Elevated 17β-estradiol(E2)is the key contributor to the disrupted sex steroid hormone homeostasis,and is significantly positively related to the clinical characteristics of T2DM patients complicated with BPH.Activating GPER by E2 via Hippo-YAP1 signaling exacerbates high glucose(HG)-induced PECs proliferation through the formation of the YAP1-TEAD4 heterodimer.Knockdown or inhibition of GPER-mediated Hippo-YAP1 signaling suppresses PECs proliferation in HG and E2 co-treated BPH-1 cells.The anti-proliferative effects of verteporfin,an inhibitor of YAP1,are blocked by YAP1 overexpression in HG and E2 co-treated BPH-1 cells.Inactivating E2/GPER/Hippo/YAP1 signaling may be effective at delaying the progression of T2DM complicated with BPH by inhibiting PECs proliferation.

Comprehensive Analysis of Estrogen Receptor 1 Dysregulation in Liver Hepatocellular Carcinoma: Implications for Prognosis and Therapeutic Targeting - A Secondary Publication

The study investigates the expression pattern and regulatory mechanisms of estrogen receptor 1 (ESR1) in liver hepatocellular carcinoma (LIHC) through comprehensive bioinformatics analysis. Utilizing UALCAN and GEPIA2 databases, significant down-regulation of ESR1 expression is observed in LIHC samples compared to normal controls, indicating its potential role in tumor progression. Further analysis reveals consistent down-regulation across different clinical variables including patient age, gender, race, and various stages of LIHC, affirming the regulatory role of ESR1 in tumor development and progression. Additionally, promoter methylation analysis demonstrates hypermethylation of ESR1 in LIHC samples, negatively correlating with its expression. This association persists across different clinical parameters, emphasizing the inverse relationship between ESR1 methylation and expression levels. Survival analysis indicates that up- regulation of ESR1 is associated with better overall survival, suggesting its potential as a prognostic biomarker in LIHC. Furthermore, genetic mutation analysis using cBioPortal reveals a spectrum of alterations in ESR1, including amplification, missense mutation, deep deletion, splice mutation, and truncating mutation, highlighting the genetic complexity of ESR1 in LIHC. These findings collectively contribute to a deeper understanding of ESR1 dysregulation in LIHC and its clinical implications as a potential therapeutic target and prognostic marker.

Prognostic implications of estrogen receptor 1 and vascular endothelial growth factor A expression in primary gallbladder carcinoma

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.

The Relationship of CyclinD1 and Estrogen Receptor Expression in the Process of Proliferation and Metastasis in Breast Neoplasm

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.

17β-Estradiol Regulates Cultured Immature Boar Sertoli Cell Proliferation via the cAMP-ERK1/2 Pathway and the Estrogen Receptor β

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-l） （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 ERaAnt did not （P〉 0.05）. Therefore, 17β- estradiol mainly promotes pig Sertoli cell proliferation via ERβ to induce cAMP production and ERK activation to promote cell proliferation.

Estrogen affects neuropathic pain through upregulating N-methyl-D-aspartate acid receptor 1 expression in the dorsal root ganglion of rats

Estrogen affects the generation and transmission of neuropathic pain,but the specific regulatory mechanism is still unclear.Activation of the N-methyl-D-aspartate acid receptor 1（NMDAR1） plays an important role in the production and maintenance of hyperalgesia and allodynia.The present study was conducted to determine whether a relationship exists between estrogen and NMDAR1 in peripheral nerve pain.A chronic sciatic nerve constriction injury model of chronic neuropathic pain was established in rats.These rats were then subcutaneously injected with 17β-estradiol,the NMDAR1 antagonist D（-）-2-amino-5-phosphonopentanoic acid（AP-5）,or both once daily for 15 days.Compared with injured drug na？ve rats,rats with chronic sciatic nerve injury that were administered estradiol showed a lower paw withdrawal mechanical threshold and a shorter paw withdrawal thermal latency,indicating increased sensitivity to mechanical and thermal pain.Estrogen administration was also associated with increased expression of NMDAR1 immunoreactivity（as assessed by immunohistochemistry） and protein（as determined by western blot assay） in spinal dorsal root ganglia.This 17β-estradiol-induced increase in NMDAR1 expression was blocked by co-administration with AP-5,whereas AP-5 alone did not affect NMDAR1 expression.These results suggest that 17β-estradiol administration significantly reduced mechanical and thermal pain thresholds in rats with chronic constriction of the sciatic nerve,and that the mechanism for this increased sensitivity may be related to the upregulation of NMDAR1 expression in dorsal root ganglia.

17β-Estradiol Regulates SKP2 Expression in Cultured Immature Boar Sertoli Cells Mainly via Estrogen Receptor β,cAMP-PKA and ERK1/2

Estrogen plays an important role in regulating testicular Sertoli cell number. Furthermore, S-phase kinase-associated protein 2 （SKP2） plays a central role in mammalian cell cycle progression. The objective of this study was to determine whether 17β-estradiol can regulate the expression of SKP2, and the Sertoli cell cycle, via estrogen receptor β （ERβ）, the cyclic adenosine monophosphate （cAMP）-protein kinase A （PKA） and extracellular signal-regulated kinase （ERK1/2） pathway. When cultured immature boar Sertoli cells were treated with 17β-estradiol, a time-dependent increase in SKP2 mRNA and protein level was observed by real-time PCR and Western blot, and 17β-estradiol activity peaked at 30 min. Treatment with ICI182780 and ERβ antagonist reduced 17β-estradiol-induced expression of SKP2 and proliferating cell nuclear antigen （PCNA）, while increasing the protein concentration of p27kip1. However, the effect of ERa antagonist on these parameters was lower than that of ICI 182780 and ERβ. Forskolin had a similar effect as 17β-estradiol on the expression of SKP2, PCNA and p27kip1, Rp-cAMP, H-89 and U0126 treatment reduced 17β-estradiol-induced changes, while H-89 also inhibited ERK1/2 activation. Therefore, 17β-estradiol mainly regulates SKP2 mRNA and protein expression via ERβ-cAMP-PKA and ERK1/2 activation. SKP2 and PCNA expression were positively correlated, while increased SKP2 expression likely resulted in p27kip1 degradation.

槲皮素通过雌激素受体下调长非编码RNA MALAT-1并发挥抗乳腺癌的作用机制

目的探索槲皮素抑制乳腺癌细胞恶性生物学行为的分子机制。方法以乳腺癌细胞系MCF-7和MB231作为研究对象,用慢病毒LV-ERα、LV-MALAT-1转染乳腺癌MB231细胞和MCF7细胞,RT-qPCR检测MALAT-1表达,Western blot检测肿瘤细胞中ERα蛋白表达,CCK-8细胞实验、平板克隆形成实验检测细胞增殖能力,PI染色法检测细胞周期,通过mRFP-GFP-LC3荧光双标腺病毒转染检测自噬水平,观察槲皮素和雌二醇对乳腺癌细胞增殖能力的影响。结果17β-雌二醇(E2)可以促进乳腺癌细胞MCF-7的增殖,而5μmol·L^(-1)槲皮素可以明显逆转E2对增殖的促进作用(P<0.05)。槲皮素对不表达雌激素受体α(estrogen receptor-α,ERα)的乳腺癌细胞MB231不表现抑制作用;而过表达ERα后,槲皮素则抑制了E2对MB231-ERα的促进作用。同时槲皮素可以抑制E2激活的MALAT-1表达;并且其抑制作用被过表达MALAT-1所逆转,包括细胞增殖,细胞周期进展以及克隆形成能力。结论槲皮素依赖于ERα的表达对乳腺癌的增殖等恶性行为起抑制作用,并且很可能是通过抑制MALAT-1的表达来发挥作用。

High mobility group protein 1: A collaborator in nucleosome dynamics and estrogen-responsive gene expression

High mobility group protein 1(HMGB1) is a multifunctional protein that interacts with DNA and chromatin to influence the regulation of transcription, DNA replication and repair and recombination. We show that HMGB1 alters the structure and stability of the canonical nucleosome(N) in a nonenzymatic,adenosine triphosphate-independent manner. As a result, the canonical nucleosome is converted to two stable, physically distinct nucleosome conformers. Although estrogen receptor(ER) does not bind to its consensus estrogen response element within a nucleosome, HMGB1 restructures the nucleosome to facilitate strong ER binding. The isolated HMGB1-restructured nucleosomes(N' and N'') remain stable and exhibit a number of characteristics that are distinctly different from the canonical nucleosome. These findings complement previous studies that showed(1) HMGB1 stimulates in vivo transcriptional activation at estrogen response elements and(2) knock down of HMGB1 expression by siR NA precipitously reduced transcriptional activation. The findings indicate that a major facet of the mechanism of HMGB1 action involves a restructuring of aspects of the nucleosome that appear to relax structural constraints within the nucleosome. The findings are extended to reveal the differences between ER and the other steroid hormone receptors. A working proposal outlines mechanisms that highlight the multiple facets that HMGB1 may utilize in restructuring the nucleosome.

G-protein-coupled estrogen receptor as a new therapeutic target for treating coronary artery disease

Coronary heart disease(CHD) continues to be the greatest mortality risk factor in the developed world. Estrogens are recognized to have great therapeutic potential to treat CHD and other cardiovascular diseases; however,a significant array of potentially debilitating side effects continues to limit their use. Moreover,recent clinical trials have indicated that long-term postmenopausal estrogen therapy may actually be detrimental to cardiovascular health. An exciting new development is the finding that the more recently discovered G-protein-coupled estrogen receptor(GPER) is expressed in coronary arteries-both in coronary endothelium and in smooth muscle within the vascular wall. Accumulating evidence indicates that GPER activation dilates coronary arteries and can also inhibit the prolif-eration and migration of coronary smooth muscle cells. Thus,selective GPER activation has the potential to increase coronary blood flow and possibly limit the debilitating consequences of coronary atherosclerotic disease. This review will highlight what is currently known regarding the impact of GPER activation on coronary arteries and the potential signaling mechanisms stimulated by GPER agonists in these vessels. A thorough understanding of GPER function in coronary arteries may promote the development of new therapies that would help alleviate CHD,while limiting the potentially dangerous side effects of estrogen therapy.

白藜芦醇通过ESR1-PI3K信号通路抑制3T3-L1细胞脂滴形成

【目的】探究白藜芦醇(RES)与雌激素受体1(ESR1)对3T3-L1细胞脂滴形成的影响及调控机制,为RES抑制脂肪沉积潜在机制的研究提供理论依据。【方法】以3T3-L1细胞为试验材料,设计并合成针对ESR1基因的小干扰RNA(siRNA),在3T3-L1细胞培养基中添加RES,以添加等量二甲基亚砜(DMSO)为对照,利用油红O染色、实时荧光定量PCR检测、Western blotting检测等分析RES与ESR1对3T3-L1细胞分化的影响。【结果】与对照组相比,RES能显著(P<0.05)减少3T3-L1细胞脂滴的生成,极显著(P<0.001)上调脂肪分解关键基因ATGL相对表达量,极显著下调(P<0.001)脂肪合成关键基因CEBPα、PPARγ及FAS相对表达量。RES能极显著(P<0.001)增加ESR1基因相对表达量,极显著(P<0.01)增加ESR1蛋白相对表达水平;同时,RES能极显著(P<0.001)下调PI3K信号通路中PI3K和AKT基因相对表达量,极显著(P<0.001)上调FOXO1基因相对表达量。干扰ESR1基因可极显著(P<0.01)增加3T3-L1细胞脂滴的生成,极显著(P<0.001)下调ATGL基因相对表达量,极显著(P<0.001)上调CEBPα、PPARγ及FAS基因相对表达量;加入RES后,干扰ESR1基因的3T3-L1细胞脂滴与未加入RES相比无显著差异(P>0.05,下同),ATGL、CEBPα、PPARγ及FAS基因相对表达量也均无显著差异。干扰ESR1基因能极显著(P<0.001)上调PI3K信号通路中PI3K和AKT基因相对表达量,极显著(P<0.001)下调FOXO1基因相对表达量;加入RES后,PI3K、AKT及FOXO1基因相对表达量与未加入RES相比均无显著差异。【结论】RES能通过ESR1-PI3K信号通路,上调脂肪分解关键基因ATGL相对表达量,下调脂肪合成关键基因CEBPα、PPARγ及FAS相对表达量,从而抑制3T3-L1细胞脂滴形成。

Quantified gene expression levels for phase Ⅰ/Ⅱ metabolizing enzyme and estrogen receptor levels in benign prostate from cohorts designated as high-risk （UK） versus low-risk （India）for adenocarcinoma at this organ site：a preliminary study

Risk of clinically significant prostate adenocarcinoma （CAP） varies worldwide,although there is a uniform prevalence of latent disease. A hormone-responsive tissue,the prostate possesses the metabolizing capacity to biotransform a variety of environmental procarcinogens or endogenous hormones. Whether such metabolizing capacity or estrogen receptor （ER） status underlies these demographic differences in susceptibility to CaP remains unclear. With appropriate ethical permission,verified-benign tissues were obtained following transurethral resection of the prostate from a high-risk region （n = 12 UK-resident Caucasians） and a typically low-risk region （n = 14 India-resident Asians）. Quantitative gene expression analysis was employed for cytochrome P450 （CYP）1B1,N-acetyltransferase （NAT）1,NAT2,catechol-O-methyl transferase （ COMT）,sulfotransferase （ SULT） 1A1,ERα,ERβ and aromatase （CYP To quantify the presence or absence of CYP1B1,ERα or ERβ,and to identify ther in situ localization,immunohistochemistry was carried out. The two cohorts had reasonably well-matched serum levels of prostate-specific antigen or hormones. Expression levels for the candidate genes investigated were similar.However,clear differences in protein levels for CYP1B1 and ERβ were noted. Staining for CYP1B1 tended to be nuclear-associated in the basal glandular epithelial cells,and in UK-resident Caucasian tissues was present at a higher （P = 0.006） level compared with that from India-resident Asians. In contrast,a higher level of positive ERβ staining was noted in prostates from India-resident Asians. These study findings point to differences in metabolizing capacity and ER status in benign prostate tissues that might modulate susceptibility to the emergence of clinically significant CaP in demographically distinct populations.

CB1 agonism prolongs time window for estrogen replacement therapy

OBJECTIVE To detect the underlying mechanism of time window for estrogen(E2)replacement treating cognitive decline.METHODS E2 begun 1 week after the ovariectomy(OVXST)or 3 months after the ovariectomy(OVXLT).Learning and memory ability were examined by trace fear memory test and inhibitory avoidance test.LTP and LTD were detected by MED64.High throughput gene expression sequencing and microRNA(miR NA) sequencing were used to detecte the differently expressed genes between OVXSTand OVXLTafter estrogen treatment.RESULTS Subcutaneous injection of E2 improved fear memory formation in both 1 week after ovariectomy(OVXST) mice or 3 months after ovariectomy(OVXLT) mice.However,for fear memory extinction,facilitated by E2 in OVXSTmice,but impaired by E2 in OVXLTmice.Further researches showed in medial prefrontal cortex(mPFC),estrogen facilitates LTD in OVXSTmice but impairs LTD in OVXLTmice.Results of highthroughput sequencings of mR NA and miRNA in mPFC from sham,OVXSTmice,E2 treated OVXST mice,OVXLTmice,and E2 treated OVXLTmice indicated decreased miR-221-5 p expression in OVXLTmice compared with OVXSTmice.In OVXLT mice,miR-221-5 p could be further reduced by E2 treatment.Additionally,miR-221-5 p targeted neuralized E3 ubiquitin protein ligase 1 a/b(Neurl1 a/b) m RNA.Decreased miR-221-5 p will promotes cannabinoid receptor 1(CB1) ubiquitination through up-regulating Neurl1 a/b protein levels in E2 treated OVXLTmice,which disrupted the retrograde endocanabinoids system.Replenishing miR-221-5 p or treating with CB1 agonist rescued the fear extinction impairment in E2 treated OVXLTmice.CONCLUSION These results uncovered a epigenetic change after long term E2 responsible for failure of E2 improving cognitive performance in OVXLTmice,moreover miR-221-5 p and CB1 agonist as potential targets for prolonging the time window for E2 replacement therapy.

Anticancer efficacy of 3-(4-isopropyl)benzylidene-8-ethoxy,6-methyl,chroman-4-one(SBL-060),a novel,dual,estrogen receptor-Akt kinase inhibitor in acute myeloid leukemia cells

Estrogen receptor(ER)αis expressed in a subset of patient-derived acute myeloid leukemia(AML)cells,whereas Akt is predominantly expressed in most types of AML.Targeting AML with dual inhibitors is a novel approach to combat the disease.Herein,we examined a novel small molecule,3-(4-isopropyl)benzylidene-8-ethoxy,6-methyl,chroman-4-one(SBL-060),capable of targeting AML cells by inhibiting ERαand Akt kinase.The chemical properties of SBL-060 were identified by proton nuclear magnetic resonance(^(1)H-NMR),^(13)C-NMR,and mass spectroscopy.In silico docking was performed using an automated protocol with AutoDock-VINA.THP-1 and HL-60 cell lines were differentiated using phorbol 12-myristate 13-acetate.ERαinhibition was assessed using ELISA.The MTT assay assessed cell viability.Flow cytometry was performed for cell cycle,apoptosis,and p-Akt analyses.Chemical analysis identified the compound as 3-(4-isopropyl)benzylidene-8-ethoxy,6-methyl,chroman-4-one,which showed high binding efficacy toward ER,with aΔG_(binding) score of−7.4 kcal/mol.SBL-060 inhibited ERα,exhibiting IC50 values of 448 and 374.3 nM in THP-1 and HL-60 cells,respectively.Regarding inhibited cell proliferation,GI50 values of SBL-060 were 244.1 and 189.9 nM for THP-1 and HL-60 cells,respectively.In addition,a dose-dependent increase in sub G_(0)/G_(1) phase cell cycle arrest and total apoptosis was observed after treatment with SBL-060 in both cell types.SBL-060 also dose-dependently increased the p-Akt-positive populations in both THP-1 and HL-60 cells.Our results indicate that SBL-060 has excellent efficacy against differentiated AML cell types by inhibiting ER and Akt kinase,warranting further preclinical evaluations.

Neurotensin Receptor 1 (NTSR1) Overexpression in Breast Carcinomas Is Common and Independent of ER/PR/Her2 Expression

Neurotensin (NT) is a 13-amino acid peptide with trophic effects on some neoplasms. Its bioactivities are mainly mediated by neurotensin receptor 1 (NTSR1). Both NT and NTSR1 were found to be upregulated in breast cancer. NT/NTSR1 thus becomes a potential therapeutic target. We studied whether any correlation exists between the expression of NTSR1 in breast carcinomas and the expression of ER, PR, and Her2. A total 85 cases of invasive ductal (62) and lobular (23) breast carcinomas were studied. Based on their ER/PR profiles, the ductal carcinomas (DCs) were subcategorized into ER+/PR+ (21), ER+/PR﹣ (20), and ER﹣/PR﹣ (21). All of the lobular carcinomas (LCs) were ER+/PR+. 21.57% of all DCs and 5.56% of LCs were Her2 positive. 77.78% of ER﹣/PR﹣ DCs were also Her2 negative (triple negative). The expression of NTSR1 was detected by immunohistochemistry and was semiquantitated (as negative, 1+, 2+, 3+). Both 2+ and 3+ were collectively defined as overexpression. The expression of NTSR1 was weak and focal in non-neoplastic mammary epithelial cells. It is increased in 74.19% of DCs (80.95% in ER+/PR+, 75% in ER+/PR﹣, and 66.67% in ER﹣/PR﹣ group), and in 95.65% of LCs. The overexpression of NTSR1 is similar between ER+ DCs and ER﹣ DCs (75% vs 66.67%, p > 0.05) as well as between PR+ DCs and PR﹣ DCs (80.95% in ER+/PR+ DCs vs 75% in ER+/PR﹣ DCs, p > 0.05). And it was seen in 77.78% of Her2+ DCs, 78.38% of Her2﹣ DCs, 94.12% of Her2﹣ LCs, and 78.57% of triple negative DCs. Overall, NTSR1 is commonly overexpressed in both ductal and lobular breast carcinomas and is independent of the ER/PR/Her2 profiles of the tumors. The present data supports the potential benefit of developing NTSR1 blockers in the adjuvant therapy of breast carcinomas, particularly for those “triple negative” tumors.

IGBP1对ER阳性乳腺癌增殖和他莫昔芬耐药的影响

目的:通过CRISPR Screen正向基因筛选技术,筛选出他莫昔芬耐药靶点基因免疫球蛋白结合蛋白1(immunoglobulin binding protein 1,IGBP1)。验证IGBP1在临床乳腺癌患者肿瘤组织中是否高表达,并探讨IGBP1对雌激素受体阳性(ER+)乳腺癌细胞增殖、细胞周期和耐药性等表型的影响,为诊断和治疗提供潜在靶点。方法:应用公共数据库分析IGBP1在乳腺癌患者肿瘤组织及配对癌旁组织中的表达是否有所不同。Kaplan-Meier Plotter用于预测IGBP1对乳腺癌患者总体生存率(the overall survival,OS)是否有所影响。应用慢病毒感染ER+乳腺癌细胞,再进行功能实验验证IGBP1过表达及敲低对ER+乳腺癌细胞增殖、细胞周期和耐药性的影响。最后用公共数据库鉴定出可能与IGBP1正、负相关的基因。结果:公共数据库的结果表明,IGBP1在乳腺癌组织中高表达。生存分析表明,IGBP1高表达的患者的OS较差。细胞功能实验显示,过表达IGBP1的细胞增殖、细胞周期明显快于对照组细胞,耐药性增强;而敲低IGBP1的结果相反。与IGBP1正相关的基因里有已知的癌基因如NOP53。结论:IGBP1在ER+乳腺癌中高表达,IGBP1的过表达和敲低均影响ER+乳腺癌细胞系的增殖、细胞周期和耐药性,提示IGBP1在ER+乳腺癌中可能能够改善其耐药,表明IGBP1可能作为ER+乳腺癌的潜在治疗靶点之一。

2型糖尿病患者血清GPER1、SESN2水平与糖尿病视网膜病变的关系研究

目的研究2型糖尿病(T2DM)患者血清G蛋白偶联雌激素受体1(GPER1)、应激诱导蛋白2(SESN2)水平与糖尿病视网膜病变(DR)的关系。方法回顾性选取2020年2月—2022年2月联勤保障部队第九四〇医院眼科诊治的T2DM患者162例为T2DM组。根据眼部检查结果,将T2DM患者分为DR亚组(n=68)和非DR亚组(n=94);根据DR病情程度,将DR患者分为增生性亚组(n=28)和非增生性亚组(n=40)。另选取同期医院健康体检者60例为健康对照组。采用酶联免疫吸附试验检测血清GPER1、SESN2水平;多因素Logistic回归分析DR的影响因素;受试者工作特征(ROC)曲线评价血清GPER1、SESN2水平对DR的预测价值。结果T2DM组血清GPER1水平高于健康对照组,血清SESN2水平低于健康对照组(t/P=36.850/<0.001,28.112/<0.001);DR亚组糖尿病病程、胰岛素抵抗指数(HOMA-IR)、血清GPER1高于非DR亚组,肾小球滤过率(eGFR)、血清SESN2低于非DR亚组(t/P=11.552/<0.001,3.078/0.009,17.226/<0.001,21.915/<0.001,11.100/<0.001);增生性DR亚组血清GPER1水平高于非增生性DR亚组,血清SESN2水平低于非增生性DR亚组(t/P=12.151/<0.001,3.534/<0.001);多因素Logistic回归结果示,糖尿病病程长、HOMA-IR高、GPER1高是DR的独立危险因素[OR(95%CI)=1.237(1.096~1.397),1.265(1.079~1.483),1.347(1.054~1.721)],eGFR高、SESN2高是DR的独立保护因素[OR(95%CI)=0.736(0.598~0.906),0.759(0.596~0.967)];血清GPER1、SESN2水平及二者联合预测DR的曲线下面积(AUC)分别为0.731、0.710、0.820,二者联合的AUC大于血清GPER1、SESN2水平单独预测(Z=4.711、4.816,P均<0.001)。结论DR患者血清GPER1升高,SESN2降低,两者均参与DR的发生发展,两者联合检测对DR的发生具有较高的预测价值。

子宫内膜癌中ERK1/2信号转导通路与雌、孕激素受体的相关性

目的检测丝裂原活化蛋白激酶(MAPK)信号通路中细胞外信号调控激酶1/2(ERK1/2)在子宫内膜癌中的表达,探讨其与雌激素受体(ER)和孕激素受体(PR)表达间的相关性。方法用免疫组化方法(SP法)检测30例子宫内膜癌石蜡标本中ERK1/2以及ER和PR的表达;同法检测20例正常子宫内膜、13例增生过长子宫内膜石蜡标本中ERK1/2的表达;对标本的染色情况做半定量分析。结果ERK1/2在正常子宫内膜、增生过长子宫内膜和子宫内膜癌中的表达水平比较,差异无统计学意义(P>0.05)。磷酸化的ERK1/2(p-ERK1/2)在ER阳性与ER阴性子宫内膜癌中的高表达率比较(76.5%vs30.8%),差异有统计学意义(P<0.05);且p-ERK1/2的高表达率与ER的表达水平呈正相关(r=0.457,P<0.05);p-ERK1/2的高表达率与PR的表达水平无相关性(P>0.05)。结论ERK1/2信号转导通路与子宫内膜恶变过程无相关性,其活化与ER表达水平呈正相关。ER可能通过ERK1/2信号通路发挥其在子宫内膜癌中的调控作用。

雌激素受体α、雌激素受体β、激活蛋白1、血管内皮生长因子在大鼠子宫内膜异位症模型中的表达及意义

目的探讨雌激素受体α(ERα)、雌激素受体β(ERβ)、激活蛋白1(AP-1)、血管内皮生长因子(VEGF)在大鼠子宫内膜异位症(EMs)模型中的表达及意义。方法采用皮下种植法建立大鼠EMs模型,选取建模成功的28只大鼠为模型组(n=28),观察大鼠EMs模型在位内膜及异位病灶的组织病理学改变,并通过免疫组织化学法检测对照组子宫内膜、模型组在位子宫内膜和异位病灶ERα、ERβ、AP-1、VEGF的表达情况。结果 1大鼠EMs模型在位内膜及异位病灶腺体、间质血管明显增加;2大鼠EMs模型的异位病灶与对照组子宫内膜间ERα阳性率比较,差异无统计学意义(P=0.107),而其在位内膜中的表达较对照组比较,差异有统计学意义(P<0.01)。ERβ、AP-1(c-jun)蛋白、VEGF在模型组在位内膜及异位病灶中阳性率与对照组比较,差异有统计学意义(P<0.01),但其在位内膜及异位病灶中的表达比较,差异无统计学意义。结论大鼠EMs模型在位内膜中ERα和ERβ均高表达,异位病灶中则仅表现为ERβ高表达,同时上调c-jun,VEGF的表达,ERβ可能在EMs的发生发展中起到较ERα更为重要的作用。

hERR1在乳腺癌中的表达及其对芳香族化酶表达的调控

目的 了解hERR1在乳腺癌及癌旁组织中的表达情况 ,以及它对芳香族化酶基因表达的调节作用。方法 收集乳腺癌患者的临床标本 ,应用RT PCR法 ,研究癌组织及相应的癌旁组织中hERR1的表达情况 ;采用瞬时转染和CAT活性分析的方法 ,研究hERR1对芳香族化酶基因表达的调节。结果 hERR1在癌组织中的表达明显高于相应的癌旁组织 (16 2 6例 ) ;hERR1以剂量依赖方式促进芳香族化酶启动子Ⅰ 3活性。结论 hERR1在体内可能起到促进乳腺癌生长的作用。