Estrogens play important roles in the development and progression of multiple tumor types.Accumulating evidence points to the significance of estrogen action not only in tumors of hormonally regulated tissues such as ...Estrogens play important roles in the development and progression of multiple tumor types.Accumulating evidence points to the significance of estrogen action not only in tumors of hormonally regulated tissues such as the breast,endometrium and ovary,but also in the development of colorectal cancer(CRC).The effects of estrogens in physiological and pathophysiological conditions are mediated by the nuclear estrogen receptorsαandβ,as well as the membranebound G protein-coupled estrogen receptor(GPER).The roles of GPER in CRC development and progression,however,remain poorly understood.Studies on the functions of GPER in the colon have shown that this estrogen receptor regulates colonic motility as well as immune responses in CRC-associated diseases,such as Crohn’s disease and ulcerative colitis.GPER is also involved in cell cycle regulation,endoplasmic reticulum stress,proliferation,apoptosis,vascularization,cell migration,and the regulation of fatty acid and estrogen metabolism in CRC cells.Thus,multiple lines of evidence suggest that GPER may play an important role in colorectal carcinogenesis.In this review,we present the current state of knowledge regarding the contribution of GPER to colon function and CRC.展开更多
Studies have confirmed a strong association between activation of the endoplasmic reticulum stress pathway and cerebral ischemia/reperfusion(I/R) injury.In this study,three key proteins in the endoplasmic reticulum st...Studies have confirmed a strong association between activation of the endoplasmic reticulum stress pathway and cerebral ischemia/reperfusion(I/R) injury.In this study,three key proteins in the endoplasmic reticulum stress pathway(glucose-regulated protein 78,caspase-12,and C/EBP homologous protein) were selected to examine the potential mechanism of endoplasmic reticulum stress in the neuroprotective effect of G protein-coupled estrogen receptor.Female Sprague-Dawley rats received ovariectomy(OVX),and then cerebral I/R rat models(OVX+ I/R) were established by middle cerebral artery occlusion.Immediately after I/R,rat models were injected with 100 μg/kg E2(OVX + I/R +E2),or 100 μg/kg G protein-coupled estrogen receptor agonist G1(OVX + I/R + G1) in the lateral ventricle.Longa scoring was used to detect neurobehavioral changes in each group.Infarct volumes were measured by 2,3,5-triphenyltetrazolium chloride staining.Morphological changes in neurons were observed by Nissl staining.Terminal dexynucleotidyl transferase-mediated nick end-labeling staining revealed that compared with the OVX + I/R group,neurological function was remarkably improved,infarct volume was reduced,number of normal Nissl bodies was dramatically increased,and number of apoptotic neurons in the hippocampus was decreased after E2 and G1 intervention.To detect the expression and distribution of endoplasmic reticulum stress-related proteins in the endoplasmic reticulum,caspase-12 distribution and expression were detected by immunofluorescence,and mRNA and protein levels of glucose-regulated protein 78,caspase-12,and C/EBP homologous protein were determined by polymerase chain reaction and western blot assay.The results showed that compared with the OVX+ I/R group,E2 and G1 treatment obviously decreased mRNA and protein expression levels of glucose-regulated protein 78,C/EBP homologous protein,and caspase-12.However,the G protein-coupled estrogen receptor antagonist G15(OVX + I/R + E2 + G15) could eliminate the effect of E2 on cerebral I/R injury.These results confirm that E2 and G protein-coupled estrogen receptor can inhibit the expression of endoplasmic reticulum stress-related proteins and neuronal apoptosis in the hippocampus,thereby improving dysfunction caused by cerebral I/R injury.Every experimental protocol was approved by the Institutional Ethics Review Board at the First Affiliated Hospital of Shihezi University School of Medicine,China(approval No.SHZ A2017-171) on February 27,2017.展开更多
目的:探讨特异性激活G蛋白偶联雌激素受体(GPER)对结直肠癌(CRC)细胞迁移的作用及其可能的机制。方法:体外培养CRC细胞RKO和SW480,使用0.5或1.0μmol/L的GPER特异性激活剂(G-1)处理CRC细胞,采用CCK-8法、划痕实验和Transwell实验分别检...目的:探讨特异性激活G蛋白偶联雌激素受体(GPER)对结直肠癌(CRC)细胞迁移的作用及其可能的机制。方法:体外培养CRC细胞RKO和SW480,使用0.5或1.0μmol/L的GPER特异性激活剂(G-1)处理CRC细胞,采用CCK-8法、划痕实验和Transwell实验分别检测G-1对CRC细胞增殖、迁移的影响。用q PCR和WB法分别检测G-1及G-1+活性氧(ROS)清除剂N-乙酰半胱氨酸(NAC)处理对RKO细胞E-钙黏素(E-Cad)、纤连蛋白(FN)m RNA和蛋白表达的影响,用流式细胞术检测RKO细胞中ROS的水平。结果:经G-1处理后RKO和SW480细胞的迁移能力均明显减弱(均P<0.05),能显著上调细胞中E-cad m RNA及蛋白表达、下调FN m RNA及蛋白表达(均P<0.05)。G-1处理能刺激RKO细胞ROS水平上升,在NAC的作用下,由G-1引起的E-cad、FN蛋白表达变化被部分逆转。结论:特异性激活GPER通过上调ROS水平抑制EMT进程,进而抑制CRC细胞的迁移。展开更多
Bisphenol A(BPA) is one of the highest volume industrial products worldwide and has been widely used to make various products as the intermediates of polycarbonate plastics and epoxy resins.Inevitably, general populat...Bisphenol A(BPA) is one of the highest volume industrial products worldwide and has been widely used to make various products as the intermediates of polycarbonate plastics and epoxy resins.Inevitably, general population has been widely exposed to BPA due to extensive use of BPAcontaining products. BPA has similar chemical structure with the natural estrogen and has been shown to induce a variety of estrogen-like endocrine effects on organism in vivo or in vitro. High doses of BPA tend to act as antagonist of estrogen receptors(ERs) by directly regulating the genomic transcription. However, BPA at environmentally relevant low-dose always disrupt the biological function via a non-genomic manner mediated by membrane receptors, rather than ERs. Although some studies had investigated the non-genomic effects of low-dose BPA, the exact molecular mechanism still remains unclear. Recently, we found that membrane G protein-coupled estrogen receptor 1 and integrin αvβ3 and its relative signal pathways participate in the induction of male germ cell proliferation and thyroid transcription disruption by the low-dose BPA. A profound understanding for the mechanism of action of the environmentally relevant BPA exposure not only contributes to objectively evaluate and predict the potential influence to human health, but also provides theoretical basis and methodological support for assessing health effects trigged by other estrogen-like environmental endocrine disruptors. Based mainly on our recent findings, this review outlines the research progress of molecular mechanism on endocrine disrupting effects of environmental low-dose BPA, existing problems and some consideration for future studies.展开更多
基金Supported by grants from the National Science Centre,Poland(2017/24/T/NZ5/00045 and2015/17/N/NZ5/00336 to Damian Jacenik)the U.S.National Institutes of Health(NIH R01CA163890 and CA194496 to Eric R.Prossnitz+3 种基金 R01 CA207051 to Ellen J.Beswick)the UNM Comprehensive Cancer Center(P30 CA118100)the Autophagy,Inflammation and Metabolism Center of Biomedical Research Excellence(P20 GM121176)Dialysis Clinic,Inc.(to Eric R.Prossnitz)
文摘Estrogens play important roles in the development and progression of multiple tumor types.Accumulating evidence points to the significance of estrogen action not only in tumors of hormonally regulated tissues such as the breast,endometrium and ovary,but also in the development of colorectal cancer(CRC).The effects of estrogens in physiological and pathophysiological conditions are mediated by the nuclear estrogen receptorsαandβ,as well as the membranebound G protein-coupled estrogen receptor(GPER).The roles of GPER in CRC development and progression,however,remain poorly understood.Studies on the functions of GPER in the colon have shown that this estrogen receptor regulates colonic motility as well as immune responses in CRC-associated diseases,such as Crohn’s disease and ulcerative colitis.GPER is also involved in cell cycle regulation,endoplasmic reticulum stress,proliferation,apoptosis,vascularization,cell migration,and the regulation of fatty acid and estrogen metabolism in CRC cells.Thus,multiple lines of evidence suggest that GPER may play an important role in colorectal carcinogenesis.In this review,we present the current state of knowledge regarding the contribution of GPER to colon function and CRC.
基金supported by the National Natural Science Foundation of China,No.81560175,81260159(both to LL)
文摘Studies have confirmed a strong association between activation of the endoplasmic reticulum stress pathway and cerebral ischemia/reperfusion(I/R) injury.In this study,three key proteins in the endoplasmic reticulum stress pathway(glucose-regulated protein 78,caspase-12,and C/EBP homologous protein) were selected to examine the potential mechanism of endoplasmic reticulum stress in the neuroprotective effect of G protein-coupled estrogen receptor.Female Sprague-Dawley rats received ovariectomy(OVX),and then cerebral I/R rat models(OVX+ I/R) were established by middle cerebral artery occlusion.Immediately after I/R,rat models were injected with 100 μg/kg E2(OVX + I/R +E2),or 100 μg/kg G protein-coupled estrogen receptor agonist G1(OVX + I/R + G1) in the lateral ventricle.Longa scoring was used to detect neurobehavioral changes in each group.Infarct volumes were measured by 2,3,5-triphenyltetrazolium chloride staining.Morphological changes in neurons were observed by Nissl staining.Terminal dexynucleotidyl transferase-mediated nick end-labeling staining revealed that compared with the OVX + I/R group,neurological function was remarkably improved,infarct volume was reduced,number of normal Nissl bodies was dramatically increased,and number of apoptotic neurons in the hippocampus was decreased after E2 and G1 intervention.To detect the expression and distribution of endoplasmic reticulum stress-related proteins in the endoplasmic reticulum,caspase-12 distribution and expression were detected by immunofluorescence,and mRNA and protein levels of glucose-regulated protein 78,caspase-12,and C/EBP homologous protein were determined by polymerase chain reaction and western blot assay.The results showed that compared with the OVX+ I/R group,E2 and G1 treatment obviously decreased mRNA and protein expression levels of glucose-regulated protein 78,C/EBP homologous protein,and caspase-12.However,the G protein-coupled estrogen receptor antagonist G15(OVX + I/R + E2 + G15) could eliminate the effect of E2 on cerebral I/R injury.These results confirm that E2 and G protein-coupled estrogen receptor can inhibit the expression of endoplasmic reticulum stress-related proteins and neuronal apoptosis in the hippocampus,thereby improving dysfunction caused by cerebral I/R injury.Every experimental protocol was approved by the Institutional Ethics Review Board at the First Affiliated Hospital of Shihezi University School of Medicine,China(approval No.SHZ A2017-171) on February 27,2017.
文摘目的:探讨特异性激活G蛋白偶联雌激素受体(GPER)对结直肠癌(CRC)细胞迁移的作用及其可能的机制。方法:体外培养CRC细胞RKO和SW480,使用0.5或1.0μmol/L的GPER特异性激活剂(G-1)处理CRC细胞,采用CCK-8法、划痕实验和Transwell实验分别检测G-1对CRC细胞增殖、迁移的影响。用q PCR和WB法分别检测G-1及G-1+活性氧(ROS)清除剂N-乙酰半胱氨酸(NAC)处理对RKO细胞E-钙黏素(E-Cad)、纤连蛋白(FN)m RNA和蛋白表达的影响,用流式细胞术检测RKO细胞中ROS的水平。结果:经G-1处理后RKO和SW480细胞的迁移能力均明显减弱(均P<0.05),能显著上调细胞中E-cad m RNA及蛋白表达、下调FN m RNA及蛋白表达(均P<0.05)。G-1处理能刺激RKO细胞ROS水平上升,在NAC的作用下,由G-1引起的E-cad、FN蛋白表达变化被部分逆转。结论:特异性激活GPER通过上调ROS水平抑制EMT进程,进而抑制CRC细胞的迁移。
基金supported by Strategic Priority Research Program of the Chinese Academy of Sciences (No.XDB01020300)the National Natural Science Foundation of China (Nos.21377158,21577149,21477139,21237005,21621064 and 21321004)
文摘Bisphenol A(BPA) is one of the highest volume industrial products worldwide and has been widely used to make various products as the intermediates of polycarbonate plastics and epoxy resins.Inevitably, general population has been widely exposed to BPA due to extensive use of BPAcontaining products. BPA has similar chemical structure with the natural estrogen and has been shown to induce a variety of estrogen-like endocrine effects on organism in vivo or in vitro. High doses of BPA tend to act as antagonist of estrogen receptors(ERs) by directly regulating the genomic transcription. However, BPA at environmentally relevant low-dose always disrupt the biological function via a non-genomic manner mediated by membrane receptors, rather than ERs. Although some studies had investigated the non-genomic effects of low-dose BPA, the exact molecular mechanism still remains unclear. Recently, we found that membrane G protein-coupled estrogen receptor 1 and integrin αvβ3 and its relative signal pathways participate in the induction of male germ cell proliferation and thyroid transcription disruption by the low-dose BPA. A profound understanding for the mechanism of action of the environmentally relevant BPA exposure not only contributes to objectively evaluate and predict the potential influence to human health, but also provides theoretical basis and methodological support for assessing health effects trigged by other estrogen-like environmental endocrine disruptors. Based mainly on our recent findings, this review outlines the research progress of molecular mechanism on endocrine disrupting effects of environmental low-dose BPA, existing problems and some consideration for future studies.
