RU-486 is an abortifacient which is used to terminate early pregnancy. It acts by blocking progesterone receptor. In our earlier study with progesterone, RU-486 was used as a progesterone receptor antagonist to find o...RU-486 is an abortifacient which is used to terminate early pregnancy. It acts by blocking progesterone receptor. In our earlier study with progesterone, RU-486 was used as a progesterone receptor antagonist to find out the mechanism of progesterone action on melanoma cells. Results indicated that the effect of progesterone was not mediated through progesterone receptor. In the course of experiments, it was observed that RU-486 by itself inhibited mouse melanoma cell growth. Further research work with RU-486 showed a dose dependent inhibition of human melanoma cell growth. The mechanism of inhibition of cell growth was due to apoptosis and this effect of RU-486 was neither mediated through progesterone receptor nor glucocorticoid receptor. This in-vitro study suggested that melanoma also could be a target for RU-486 action, apart from breast, ovary and prostate cancers.展开更多
Background:Steroid receptor-associated and regulated protein(SRARP)suppresses tumor progression and modulates steroid receptor signaling by interacting with estrogen receptors and androgen receptors in breast cancer.I...Background:Steroid receptor-associated and regulated protein(SRARP)suppresses tumor progression and modulates steroid receptor signaling by interacting with estrogen receptors and androgen receptors in breast cancer.In endometrial cancer(EC),progesterone receptor(PR)signaling is crucial for responsiveness to progestin therapy.The aim of this study was to investigate the role of SRARP in tumor progression and PR signaling in EC.Methods:Ribonucleic acid sequencing data from the Cancer Genome Atlas,Clinical Proteomic Tumor Analysis Consortium,and Gene Expression Omnibus were used to analyze the clinical significance of SRARP and its correlation with PR expression in EC.The correlation between SRARP and PR expression was validated in EC samples obtained from Peking University People’s Hospital.SRARP function was investigated by lentivirus-mediated overexpression in Ishikawa and HEC-50B cells.Cell Counting Kit-8 assays,cell cycle analyses,wound healing assays,and Transwell assays were used to evaluate cell proliferation,migration,and invasion.Western blotting and quantitative real-time polymerase chain reaction were used to evaluate gene expression.The effects of SRARP on the regulation of PR signaling were determined by co-immunoprecipitation,PR response element(PRE)luciferase reporter assay,and PR downstream gene detection.Results:Higher SRARP expression was significantly associated with better overall survival and disease-free survival and less aggressive EC types.SRARP overexpression suppressed growth,migration,and invasion in EC cells,increased E-cadherin expression,and decreased N-cadherin and Wnt family member 7A(WNT7A)expression.SRARP expression was positively correlated with PR expression in EC tissues.In SRARP-overexpressing cells,PR isoform B(PRB)was upregulated and SRARP bound to PRB.Significant increases in PRE-based luciferase activity and expression levels of PR target genes were observed in response to medroxyprogesterone acetate.Conclusions:This study illustrates that SRARP exerts a tumor-suppressive effect by inhibiting the epithelial-mesenchymal transition via Wnt signaling in EC.In addition,SRARP positively modulates PR expression and interacts with PR to regulate PR downstream target genes.展开更多
Background:The 21-gene recurrence score(RS)assay has been recommended by major guidelines for treatment decision in hormone receptor(HR)-positive early breast cancer(EBC).However,the genomic assay is not accessible an...Background:The 21-gene recurrence score(RS)assay has been recommended by major guidelines for treatment decision in hormone receptor(HR)-positive early breast cancer(EBC).However,the genomic assay is not accessible and affordable worldwide.Alternatively,an increasing number of studies have shown that traditional immunohistochemistry(IHC)can partially or even completely replace the role of the 21-gene genomic assay.Here,we developed and validated a predictive model(IHC3 model)combining the Ki-67 index,progesterone receptor(PR)expression,histologic grade,and tumor size to predict the recurrence risk of HR-positive EBC.Methods:The data from 389 patients(development set)with HR-positive,human epidermal growth factor receptor 2-negative,lymph node non-metastasized invasive breast cancer were used to construct the IHC3 model based on the Surexam®21-gene RS and the TAILORx clinical trial criteria.An additional 146 patients with the same characteristics constituted the validation set.The predictive accuracy of the IHC3 model was compared with that of Orucevic et al.’s nomogram.Invasive diseasefree survival(IDFS)was analyzed in the IHC3 predictive low-recurrence risk(pLR)group and the predictive high-recurrence risk(pHR)group.The Pearson chi-square test,Fisher exact test,and log-rank test were used for analysis.Results:The pLR and pHR group could be easily stratified using the decision tree model without network dependence.The accuracies of the IHC3 model were 86.1%in the development set and 87.7%in the validation set.The predictive accuracy of the IHC3 model and Orucevic et al.’s nomogram for the whole cohort was 86.5%and 86.9%,respectively.After a 52-month of median follow-up,a significant difference was found in IDFS between of the IHC3 pLR and the pHR groups(P=0.001)but not in the IDFS between the low-and high-recurrence risk groups according to the Surexam®21-gene RS and the TAILORx clinical trial criteria(P=0.556)or 21-gene binary RS group(P=0.511).Conclusions:The proposed IHC3 model could reliably predict low and high recurrence risks in most HR-positive EBC patients.This easy-to-use predictive model may be a reliable replacement for the 21-gene genomic assay in patients with EBC who have no access to or cannot afford the 21-gene genomic assay.展开更多
Background:Ultrasound-triggered microbubble destruction(UTMD) is a widely used noninvasive technology in both military and civilian medicine,which could enhance radiosensitivity of various tumors.However,little inform...Background:Ultrasound-triggered microbubble destruction(UTMD) is a widely used noninvasive technology in both military and civilian medicine,which could enhance radiosensitivity of various tumors.However,little information is available regarding the effects of UTMD on radiotherapy for glioblastoma or the underlying mechanism.This study aimed to delineate the effect of UTMD on the radiosensitivity of glioblastoma and the potential involvement of autophagy.Methods:GL261,U251 cells and orthotopic glioblastoma-bearing mice were treated with ionizing radiation(IR) or IR plus UTMD.Autophagy was observed by confocal microscopy and transmission electron microscopy.Western blotting and immunofluorescence analysis were used to detect progesterone receptor membrane component 1(PGRMC1),light chain 3 beta 2(LC3B2) and sequestosome 1(SQSTM1/p62) levels.Lentiviral vectors or siRNAs transfection,and fluorescent probes staining were used to explore the underlying mechanism.Results:UTMD enhanced the radiosensitivity of glioblastoma in vitro and in vivo(P<0.01).UTMD inhibited autophagic flux by disrupting autophagosome-lysosome fusion without impairing lysosomal function or autophagosome synthesis in IR-treated glioblastoma cells.Suppression of autophagy by 3-methyladenine,bafilomycin A1 or ATG5 siRNA had no significant effect on UTMD-induced radiosensitization in glioblastoma cells(P<0.05).Similar results were found when autophagy was induced by rapamycin or ATG5 overexpression(P>0.05).Furthermore,UTMD inhibited PGRMC1expression and binding with LC3B2 in IR-exposed glioblastoma cells(P<0.01).PGRMC1 inhibitor AG-205 or PGRMC1siRNA pretreatment enhanced UTMD-induced LC3B2 and p62 accumulation in IR-exposed glioblastoma cells,thereby promoting UTMD-mediated radiosensitization(P<0.05).Moreover,PGRMC1 overexpression abolished UTMD-caused blockade of autophagic degradation,subsequently inhibiting UTMD-induced radiosensitization of glioblastoma cells.Finally,compared with IR plus UTMD group,PGRMC1 overexpression significantly increased tumor size [(3.8±1.1) mm^(2)vs.(8.0±1.9) mm^(2),P<0.05] and decreased survival time [(67.2±2.6) d vs.(40.0±1.2) d,P=0.0026] in glioblastoma-bearing mice.Conclusions:UTMD enhanced the radiosensitivity of glioblastoma partially by disrupting PGRMC1-mediated autophagy.展开更多
Objective To analyze the relationship of the expression level of estrogen receptor(ER),progesterone receptor(PR)and human epidermal growth factor receptor-2(HER-2,c-erbB-2)of breast invasive ductal carcinoma(IDC)with ...Objective To analyze the relationship of the expression level of estrogen receptor(ER),progesterone receptor(PR)and human epidermal growth factor receptor-2(HER-2,c-erbB-2)of breast invasive ductal carcinoma(IDC)with ultrasonographic characteristics.Methods Totally 104 patients with IDCs confirmed pathologically were involved in this study.ER,PR and c-erbB-2 expression in the IDC specimens was determined by immunohistochemical staining technique.The correlation between the ultrasonographic features and the positive expression of ER,PR or c-erbB-2 was analyzed.Results The positive expression rate of ER and PR in the group with tumor spiculation sign and posterior acoustic attenuation was higher than that in the group without.The positive expression rate of ER differed significantly(P<0.05)while that of PR did not(P>0.05).The over-expression rate of c-erbB-2 in the group of microcalcification,sufficient blood flow and axillary lymph node metastasis was higher than that in the group of non-microcalcification,deficient blood flow or without axillary lymph node metastasis(P<0.05).The expression of ER,PR and c-erbB-2 was not related to the size of tumor(P>0.05).Conclusion The expression of ER and c-erbB-2 is closely related to the ultrasonographic characteristics of IDC,which may,to some extent,reflect the expression level of ER and c-erbB-2.展开更多
Uterine fibroids are common in females of reproductive age and substantially affecting fertility and quality of life. Current management strategies mainly involve surgical interventions. For treatment, options availab...Uterine fibroids are common in females of reproductive age and substantially affecting fertility and quality of life. Current management strategies mainly involve surgical interventions. For treatment, options available are surgical and non-surgical, but the mode of management leans on several factors, such as severity of symptoms, patient’s age, myoma characteristics, desire to preserve uterus and fertility. Alternative approach to surgery for the treatment of symptomatic females with uterine myomas has been recognized. Ulipristal acetate (UPA) has been the first selective progesterone-receptor modulator (SPRM) approved for the pre-operative and long-term management of uterine fibroids. There are evidences promoting an important role for progesterone pathways in the pathophysiology of uterine fibroids which supports the use of ulipristal acetate. The availability of alternative choices to surgical intervention is very necessary especially for those willing to preserve uterus and fertility. One of the alternatives is with ulipristal acetate, which has been proven to treat fibroid symptoms effectively.展开更多
Objective:Clinically,low-dose aspirin and progesterone are frequently used to prevent pregnancy loss.We investigated the effect of these drugs on the biological behavior of human extravillous trophoblasts in vitro.Met...Objective:Clinically,low-dose aspirin and progesterone are frequently used to prevent pregnancy loss.We investigated the effect of these drugs on the biological behavior of human extravillous trophoblasts in vitro.Methods:HTR-8/SVneo cells were cultured in vitro and treated with different concentrations of aspirin and progesterone.The proliferation,invasion,and apoptosis of HTR-8/SVneo cells were assessed using a cell counting Kit-8 assay,Matrigel Transwell assay,and Hoechst staining,respectively.Reverse transcriptase polymerase chain reaction was used to verify the expression of related genes.Reactive oxygen species(ROS)levels were detected using the 2,7-dichlorofluorescin diacetate assay.Results:Low-dose aspirin alone,progesterone alone,or aspirin plus progesterone upregulated the proliferation and invasion and decreased the apoptosis of HTR-8/SVneo cells.Moreover,the expression of marker of proliferation Ki-67(MKI67),matrix metalloproteinases 2(MMP2),and MMP9 was increased.In addition,low-dose aspirin plus progesterone exerted stronger anti-apoptosis effects than low-dose aspirin and progesterone alone.Interestingly,aspirin upregulated the expression of progesterone receptor(PGR).Treatment with hydrogen peroxide(H_(2)O_(2))promoted ROS production in HTR-8/SVneo cells;however,low-dose aspirin plus progesterone significantly restricted H_(2)O_(2)-mediated ROS production and apoptosis in HTR-8/SVneo cells.Conclusions:These data suggest that low-dose aspirin and progesterone promote proliferation and invasion and cooperatively reduce oxidative stress and apoptosis in trophoblasts in vitro.These results may provide an experimental basis for the combined application of aspirin and progesterone to prevent unexplained recurrent spontaneous miscarriage,especially in patients with trophoblast dysfunction.展开更多
Breast cancer is the most common cancer in the world.Despite advances in early detection and understanding of the molecular bases of breast cancer biology,approximately 30%of all patients with early-stage breast cance...Breast cancer is the most common cancer in the world.Despite advances in early detection and understanding of the molecular bases of breast cancer biology,approximately 30%of all patients with early-stage breast cancer have metastatic disease.Breast cancers are comprised of molecularly distinct subtypes that respond differently to pathway-targeted therapies and neoadjuvant systemic therapy.However,no tumor response is observed in some cases and development of resistance is most commonly seen in patients with heterogeneous breast cancer subtype.To offer better treatment with increased efficacy and low toxicity of selecting therapies,new technologies that incorporate clinical and molecular characteristics of intratumoral heterogeneity have been investigated.This short review provides some examples of integrative omics approaches(genome,epigenome,transcriptome,immune profiling)and mathematical/computational analyses that provide mechanistic and clinically relevant insights into underlying differences in breast cancer subtypes and patients’responses to specific therapies.展开更多
Background::Re-biopsy of metastasis in advanced breast cancer(ABC)has become an international convention to assist the diagnosis and evaluation of tumor heterogeneity.This study aimed to detect diagnostic diversity an...Background::Re-biopsy of metastasis in advanced breast cancer(ABC)has become an international convention to assist the diagnosis and evaluation of tumor heterogeneity.This study aimed to detect diagnostic diversity and inconsistencies among estrogen receptor(ER),progesterone receptor(PR),and human epidermal growth factor receptor 2(HER2)expression levels between primary and metastatic lesions.Methods::We conducted a retrospective analysis of 1670 cases of ABC patients who had undergone at least one lesion re-biopsy from January 2010 to December 2018.The pathological diagnosis of biopsies,distribution of biopsy sites,and severe puncture complications at each site were collected.In addition,the inconsistency rates and related factors of ER,PR,and HER2 expression between primary and metastatic lesions were analyzed fully considering patients’demographic profiles and disease characteristics.Results::In total,1670 cases of breast cancer(BC)patients diagnosed by pathology underwent one to four biopsies of recurrences or metastases in different sites or at different stages during the rescue treatment,producing 2019 histopathological specimens which were analyzed in the study.Pathological diagnosis showed that eight patients had benign pathological diagnoses,11 patients had second primary malignant tumors but without recurrences of breast cancer,and 17 patients had pathologically confirmed breast cancer recurrences combined with second primary cancer.In 1173 patients who presented ER,PR,and HER2 expressions in primary and metastatic lesions,the inconsistency rates of ER,PR,and HER2 were 17.5%(205/1173),31.3%(367/1173),and 13.9%(163/1173),respectively.The multivariate analysis showed that the age at the onset of breast cancer or adjuvant endocrine therapy was an independent factor affecting changes in PR expression level.Except one liver puncture with local hemorrhage and two lung punctures with hemopneumothorax,no other severe puncture complications occurred in 1950 non-surgical rebiopsies.Conclusions::The pathological diagnosis of metastasis re-biopsy of ABC was diverse,and the ER,PR,and HER2 expression levels were inconsistent between primary and metastatic lesions.Therefore,more attention should be paid to perform biopsies of relapsed and metastatic breast cancers routinely in clinical practice.展开更多
OBJECTIVE: To investigate the hormone-like activities of Kuntai capsule(KTC) in the uteri of ovariectomized rats and immature rabbits.METHODS: Following bilateral ovariectomy, rats were randomly divided into six group...OBJECTIVE: To investigate the hormone-like activities of Kuntai capsule(KTC) in the uteri of ovariectomized rats and immature rabbits.METHODS: Following bilateral ovariectomy, rats were randomly divided into six groups including sham group, control group, estradiol valerate group, KTC 0.24, 0.6, and 1.5 g/kg groups. The rats were treated with 0.5% CMC-Na, estradiol valerate and KTC(0.24, 0.6, and 1.5 g/kg), respectively for 28 consecutive days. Then the estrous cycle, uterine changes and pathological changes were examined.Serum levels of estradiol(E2), and progesterone(P4)were measured by enzyme-linked immunosorbent assay(ELISA). Protein levels of estradiol receptor(ER), progesterone receptor(PR), vascular endothelial growth factor(VEGF), proliferating cell nuclear antigen(PCNA) and nuclear-associated antigen-67(Ki-67) in uterine tissues were detected by western blot. Immature rabbits were estrogen-primed prior to intragastric administration with KTC for 6 d consecutively. Then, the uteri underwent hematoxylin-eosin staining to observe endometrial transformation.RESULTS: Compared with the control group, 0.6and 1.5 g/kg KTC markedly decreased the uterine organ coefficient and endometrial thickness(P <0.05). The serum level of P4 was increased in the KTC 0.6 g/kg group(P < 0.05). There were no significant variations in the serum level of E2 in the KTC groups compared with the control group. ERβ, but not ERα, was markedly upregulated after KTC administration(P < 0.05). Furthermore, 1.5 g/kg KTC significantly decreased the protein level of PRA(P <0.05) and 0.6 g/kg KTC increased the protein level of PRB in the uteri(P < 0.05). VEGF was highly expressed after treatment with 0.24 and 0.6 g/kg KTC,and Ki-67 was markedly reduced in ovariectomized rats treated with 1.5 g/kg KTC. No difference was found in the expression of PCNA. KTC 0.24 and0.6 g/kg promoted endometrial transformation in immature rabbit uteri.CONCLUSION: KTC does not demonstrate obvious estrogen-like effect on uteri after ovariectomy, but it does exhibit weak progestogen-like effect, by which mechanism of action is yet to be further investigated.展开更多
Breast cancer incidence has increased and become the world’s most prevalent cancer,which is related to abnormal development of mammary glands and thought to be influenced by environment endocrine disruptors such as b...Breast cancer incidence has increased and become the world’s most prevalent cancer,which is related to abnormal development of mammary glands and thought to be influenced by environment endocrine disruptors such as bisphenol A(BPA).However,whether its substitution,bisphenol B(BPB),has similar effects remains a concern.In the present study,a maternal exposure model of ICR mice combined time-series RNA-seq analysis was established to explore the underlying correlation among maternal BPB exposure(300μg/kg body weight),mammary gland development,and long-term breast health in offspring.The results showed that BPB exposure disrupted hormonal homeostasis of the female offspring but did not affect the branch development of mammary glands in a time-dependent manner.However,at postnatal day 90(PND90),BPB exposure resulted in duct dilatation,lobular hyperplasia,and inflammatory cell infiltration and increased the number of hormone receptor-expressing(HR+)luminal cells in offspring.Further,the differentially expressed genes in time-series analysis of RNA-seq for mammary glands of the female offspring were enriched in the morphogenesis of branching structures,branching epithelium,and branching morphogenesis of epithelial tubes,which are always considered gland development.Interestingly,the results of RNA-seq also suggested that progesterone receptor(Pgr)mRNA expression in the BPB group was elevated at PND90,and breast cancer related genes such as GATA binding protein 3(Gata3)and epidermal growth factor receptor(Egfr)were also altered.These findings suggested that maternal BPB exposure did not accelerate mammary gland development or lead to obvious morphological anomalies of offspring,but it induced pathological changes and altered cancer related gene expression in adult offspring breast.展开更多
文摘RU-486 is an abortifacient which is used to terminate early pregnancy. It acts by blocking progesterone receptor. In our earlier study with progesterone, RU-486 was used as a progesterone receptor antagonist to find out the mechanism of progesterone action on melanoma cells. Results indicated that the effect of progesterone was not mediated through progesterone receptor. In the course of experiments, it was observed that RU-486 by itself inhibited mouse melanoma cell growth. Further research work with RU-486 showed a dose dependent inhibition of human melanoma cell growth. The mechanism of inhibition of cell growth was due to apoptosis and this effect of RU-486 was neither mediated through progesterone receptor nor glucocorticoid receptor. This in-vitro study suggested that melanoma also could be a target for RU-486 action, apart from breast, ovary and prostate cancers.
基金supported by grants from the National Key Technology R&D Program of China(Nos.2019YFC1005200 and 2019YFC1005201).
文摘Background:Steroid receptor-associated and regulated protein(SRARP)suppresses tumor progression and modulates steroid receptor signaling by interacting with estrogen receptors and androgen receptors in breast cancer.In endometrial cancer(EC),progesterone receptor(PR)signaling is crucial for responsiveness to progestin therapy.The aim of this study was to investigate the role of SRARP in tumor progression and PR signaling in EC.Methods:Ribonucleic acid sequencing data from the Cancer Genome Atlas,Clinical Proteomic Tumor Analysis Consortium,and Gene Expression Omnibus were used to analyze the clinical significance of SRARP and its correlation with PR expression in EC.The correlation between SRARP and PR expression was validated in EC samples obtained from Peking University People’s Hospital.SRARP function was investigated by lentivirus-mediated overexpression in Ishikawa and HEC-50B cells.Cell Counting Kit-8 assays,cell cycle analyses,wound healing assays,and Transwell assays were used to evaluate cell proliferation,migration,and invasion.Western blotting and quantitative real-time polymerase chain reaction were used to evaluate gene expression.The effects of SRARP on the regulation of PR signaling were determined by co-immunoprecipitation,PR response element(PRE)luciferase reporter assay,and PR downstream gene detection.Results:Higher SRARP expression was significantly associated with better overall survival and disease-free survival and less aggressive EC types.SRARP overexpression suppressed growth,migration,and invasion in EC cells,increased E-cadherin expression,and decreased N-cadherin and Wnt family member 7A(WNT7A)expression.SRARP expression was positively correlated with PR expression in EC tissues.In SRARP-overexpressing cells,PR isoform B(PRB)was upregulated and SRARP bound to PRB.Significant increases in PRE-based luciferase activity and expression levels of PR target genes were observed in response to medroxyprogesterone acetate.Conclusions:This study illustrates that SRARP exerts a tumor-suppressive effect by inhibiting the epithelial-mesenchymal transition via Wnt signaling in EC.In addition,SRARP positively modulates PR expression and interacts with PR to regulate PR downstream target genes.
基金This study was funded by the science and technology commission of Beijing:Optimization of breast cancer screening program for 35-75 years old women in Beijing(Grant No.D161100000816005)。
文摘Background:The 21-gene recurrence score(RS)assay has been recommended by major guidelines for treatment decision in hormone receptor(HR)-positive early breast cancer(EBC).However,the genomic assay is not accessible and affordable worldwide.Alternatively,an increasing number of studies have shown that traditional immunohistochemistry(IHC)can partially or even completely replace the role of the 21-gene genomic assay.Here,we developed and validated a predictive model(IHC3 model)combining the Ki-67 index,progesterone receptor(PR)expression,histologic grade,and tumor size to predict the recurrence risk of HR-positive EBC.Methods:The data from 389 patients(development set)with HR-positive,human epidermal growth factor receptor 2-negative,lymph node non-metastasized invasive breast cancer were used to construct the IHC3 model based on the Surexam®21-gene RS and the TAILORx clinical trial criteria.An additional 146 patients with the same characteristics constituted the validation set.The predictive accuracy of the IHC3 model was compared with that of Orucevic et al.’s nomogram.Invasive diseasefree survival(IDFS)was analyzed in the IHC3 predictive low-recurrence risk(pLR)group and the predictive high-recurrence risk(pHR)group.The Pearson chi-square test,Fisher exact test,and log-rank test were used for analysis.Results:The pLR and pHR group could be easily stratified using the decision tree model without network dependence.The accuracies of the IHC3 model were 86.1%in the development set and 87.7%in the validation set.The predictive accuracy of the IHC3 model and Orucevic et al.’s nomogram for the whole cohort was 86.5%and 86.9%,respectively.After a 52-month of median follow-up,a significant difference was found in IDFS between of the IHC3 pLR and the pHR groups(P=0.001)but not in the IDFS between the low-and high-recurrence risk groups according to the Surexam®21-gene RS and the TAILORx clinical trial criteria(P=0.556)or 21-gene binary RS group(P=0.511).Conclusions:The proposed IHC3 model could reliably predict low and high recurrence risks in most HR-positive EBC patients.This easy-to-use predictive model may be a reliable replacement for the 21-gene genomic assay in patients with EBC who have no access to or cannot afford the 21-gene genomic assay.
基金supported by the National Natural Science Foundation of China (82073544 and 81971774)the Chongqing Talent Project (CQYC2019)the Chongqing Chief Expert Program in Medicine (CQYC2018)。
文摘Background:Ultrasound-triggered microbubble destruction(UTMD) is a widely used noninvasive technology in both military and civilian medicine,which could enhance radiosensitivity of various tumors.However,little information is available regarding the effects of UTMD on radiotherapy for glioblastoma or the underlying mechanism.This study aimed to delineate the effect of UTMD on the radiosensitivity of glioblastoma and the potential involvement of autophagy.Methods:GL261,U251 cells and orthotopic glioblastoma-bearing mice were treated with ionizing radiation(IR) or IR plus UTMD.Autophagy was observed by confocal microscopy and transmission electron microscopy.Western blotting and immunofluorescence analysis were used to detect progesterone receptor membrane component 1(PGRMC1),light chain 3 beta 2(LC3B2) and sequestosome 1(SQSTM1/p62) levels.Lentiviral vectors or siRNAs transfection,and fluorescent probes staining were used to explore the underlying mechanism.Results:UTMD enhanced the radiosensitivity of glioblastoma in vitro and in vivo(P<0.01).UTMD inhibited autophagic flux by disrupting autophagosome-lysosome fusion without impairing lysosomal function or autophagosome synthesis in IR-treated glioblastoma cells.Suppression of autophagy by 3-methyladenine,bafilomycin A1 or ATG5 siRNA had no significant effect on UTMD-induced radiosensitization in glioblastoma cells(P<0.05).Similar results were found when autophagy was induced by rapamycin or ATG5 overexpression(P>0.05).Furthermore,UTMD inhibited PGRMC1expression and binding with LC3B2 in IR-exposed glioblastoma cells(P<0.01).PGRMC1 inhibitor AG-205 or PGRMC1siRNA pretreatment enhanced UTMD-induced LC3B2 and p62 accumulation in IR-exposed glioblastoma cells,thereby promoting UTMD-mediated radiosensitization(P<0.05).Moreover,PGRMC1 overexpression abolished UTMD-caused blockade of autophagic degradation,subsequently inhibiting UTMD-induced radiosensitization of glioblastoma cells.Finally,compared with IR plus UTMD group,PGRMC1 overexpression significantly increased tumor size [(3.8±1.1) mm^(2)vs.(8.0±1.9) mm^(2),P<0.05] and decreased survival time [(67.2±2.6) d vs.(40.0±1.2) d,P=0.0026] in glioblastoma-bearing mice.Conclusions:UTMD enhanced the radiosensitivity of glioblastoma partially by disrupting PGRMC1-mediated autophagy.
文摘Objective To analyze the relationship of the expression level of estrogen receptor(ER),progesterone receptor(PR)and human epidermal growth factor receptor-2(HER-2,c-erbB-2)of breast invasive ductal carcinoma(IDC)with ultrasonographic characteristics.Methods Totally 104 patients with IDCs confirmed pathologically were involved in this study.ER,PR and c-erbB-2 expression in the IDC specimens was determined by immunohistochemical staining technique.The correlation between the ultrasonographic features and the positive expression of ER,PR or c-erbB-2 was analyzed.Results The positive expression rate of ER and PR in the group with tumor spiculation sign and posterior acoustic attenuation was higher than that in the group without.The positive expression rate of ER differed significantly(P<0.05)while that of PR did not(P>0.05).The over-expression rate of c-erbB-2 in the group of microcalcification,sufficient blood flow and axillary lymph node metastasis was higher than that in the group of non-microcalcification,deficient blood flow or without axillary lymph node metastasis(P<0.05).The expression of ER,PR and c-erbB-2 was not related to the size of tumor(P>0.05).Conclusion The expression of ER and c-erbB-2 is closely related to the ultrasonographic characteristics of IDC,which may,to some extent,reflect the expression level of ER and c-erbB-2.
文摘Uterine fibroids are common in females of reproductive age and substantially affecting fertility and quality of life. Current management strategies mainly involve surgical interventions. For treatment, options available are surgical and non-surgical, but the mode of management leans on several factors, such as severity of symptoms, patient’s age, myoma characteristics, desire to preserve uterus and fertility. Alternative approach to surgery for the treatment of symptomatic females with uterine myomas has been recognized. Ulipristal acetate (UPA) has been the first selective progesterone-receptor modulator (SPRM) approved for the pre-operative and long-term management of uterine fibroids. There are evidences promoting an important role for progesterone pathways in the pathophysiology of uterine fibroids which supports the use of ulipristal acetate. The availability of alternative choices to surgical intervention is very necessary especially for those willing to preserve uterus and fertility. One of the alternatives is with ulipristal acetate, which has been proven to treat fibroid symptoms effectively.
基金This study was supported by the National Natural Science Foundation of China(No.31970798,31671200,82072872)the Innovation-oriented Science and Technology Grant from NPFPC Key Laboratory of Reproduction Regulation(CX2017-2)+1 种基金the Program for Zhouxue of Fudan University(JIF157602)the Support Project for Original Personalized Research of Fudan University.
文摘Objective:Clinically,low-dose aspirin and progesterone are frequently used to prevent pregnancy loss.We investigated the effect of these drugs on the biological behavior of human extravillous trophoblasts in vitro.Methods:HTR-8/SVneo cells were cultured in vitro and treated with different concentrations of aspirin and progesterone.The proliferation,invasion,and apoptosis of HTR-8/SVneo cells were assessed using a cell counting Kit-8 assay,Matrigel Transwell assay,and Hoechst staining,respectively.Reverse transcriptase polymerase chain reaction was used to verify the expression of related genes.Reactive oxygen species(ROS)levels were detected using the 2,7-dichlorofluorescin diacetate assay.Results:Low-dose aspirin alone,progesterone alone,or aspirin plus progesterone upregulated the proliferation and invasion and decreased the apoptosis of HTR-8/SVneo cells.Moreover,the expression of marker of proliferation Ki-67(MKI67),matrix metalloproteinases 2(MMP2),and MMP9 was increased.In addition,low-dose aspirin plus progesterone exerted stronger anti-apoptosis effects than low-dose aspirin and progesterone alone.Interestingly,aspirin upregulated the expression of progesterone receptor(PGR).Treatment with hydrogen peroxide(H_(2)O_(2))promoted ROS production in HTR-8/SVneo cells;however,low-dose aspirin plus progesterone significantly restricted H_(2)O_(2)-mediated ROS production and apoptosis in HTR-8/SVneo cells.Conclusions:These data suggest that low-dose aspirin and progesterone promote proliferation and invasion and cooperatively reduce oxidative stress and apoptosis in trophoblasts in vitro.These results may provide an experimental basis for the combined application of aspirin and progesterone to prevent unexplained recurrent spontaneous miscarriage,especially in patients with trophoblast dysfunction.
文摘Breast cancer is the most common cancer in the world.Despite advances in early detection and understanding of the molecular bases of breast cancer biology,approximately 30%of all patients with early-stage breast cancer have metastatic disease.Breast cancers are comprised of molecularly distinct subtypes that respond differently to pathway-targeted therapies and neoadjuvant systemic therapy.However,no tumor response is observed in some cases and development of resistance is most commonly seen in patients with heterogeneous breast cancer subtype.To offer better treatment with increased efficacy and low toxicity of selecting therapies,new technologies that incorporate clinical and molecular characteristics of intratumoral heterogeneity have been investigated.This short review provides some examples of integrative omics approaches(genome,epigenome,transcriptome,immune profiling)and mathematical/computational analyses that provide mechanistic and clinically relevant insights into underlying differences in breast cancer subtypes and patients’responses to specific therapies.
文摘Background::Re-biopsy of metastasis in advanced breast cancer(ABC)has become an international convention to assist the diagnosis and evaluation of tumor heterogeneity.This study aimed to detect diagnostic diversity and inconsistencies among estrogen receptor(ER),progesterone receptor(PR),and human epidermal growth factor receptor 2(HER2)expression levels between primary and metastatic lesions.Methods::We conducted a retrospective analysis of 1670 cases of ABC patients who had undergone at least one lesion re-biopsy from January 2010 to December 2018.The pathological diagnosis of biopsies,distribution of biopsy sites,and severe puncture complications at each site were collected.In addition,the inconsistency rates and related factors of ER,PR,and HER2 expression between primary and metastatic lesions were analyzed fully considering patients’demographic profiles and disease characteristics.Results::In total,1670 cases of breast cancer(BC)patients diagnosed by pathology underwent one to four biopsies of recurrences or metastases in different sites or at different stages during the rescue treatment,producing 2019 histopathological specimens which were analyzed in the study.Pathological diagnosis showed that eight patients had benign pathological diagnoses,11 patients had second primary malignant tumors but without recurrences of breast cancer,and 17 patients had pathologically confirmed breast cancer recurrences combined with second primary cancer.In 1173 patients who presented ER,PR,and HER2 expressions in primary and metastatic lesions,the inconsistency rates of ER,PR,and HER2 were 17.5%(205/1173),31.3%(367/1173),and 13.9%(163/1173),respectively.The multivariate analysis showed that the age at the onset of breast cancer or adjuvant endocrine therapy was an independent factor affecting changes in PR expression level.Except one liver puncture with local hemorrhage and two lung punctures with hemopneumothorax,no other severe puncture complications occurred in 1950 non-surgical rebiopsies.Conclusions::The pathological diagnosis of metastasis re-biopsy of ABC was diverse,and the ER,PR,and HER2 expression levels were inconsistent between primary and metastatic lesions.Therefore,more attention should be paid to perform biopsies of relapsed and metastatic breast cancers routinely in clinical practice.
文摘OBJECTIVE: To investigate the hormone-like activities of Kuntai capsule(KTC) in the uteri of ovariectomized rats and immature rabbits.METHODS: Following bilateral ovariectomy, rats were randomly divided into six groups including sham group, control group, estradiol valerate group, KTC 0.24, 0.6, and 1.5 g/kg groups. The rats were treated with 0.5% CMC-Na, estradiol valerate and KTC(0.24, 0.6, and 1.5 g/kg), respectively for 28 consecutive days. Then the estrous cycle, uterine changes and pathological changes were examined.Serum levels of estradiol(E2), and progesterone(P4)were measured by enzyme-linked immunosorbent assay(ELISA). Protein levels of estradiol receptor(ER), progesterone receptor(PR), vascular endothelial growth factor(VEGF), proliferating cell nuclear antigen(PCNA) and nuclear-associated antigen-67(Ki-67) in uterine tissues were detected by western blot. Immature rabbits were estrogen-primed prior to intragastric administration with KTC for 6 d consecutively. Then, the uteri underwent hematoxylin-eosin staining to observe endometrial transformation.RESULTS: Compared with the control group, 0.6and 1.5 g/kg KTC markedly decreased the uterine organ coefficient and endometrial thickness(P <0.05). The serum level of P4 was increased in the KTC 0.6 g/kg group(P < 0.05). There were no significant variations in the serum level of E2 in the KTC groups compared with the control group. ERβ, but not ERα, was markedly upregulated after KTC administration(P < 0.05). Furthermore, 1.5 g/kg KTC significantly decreased the protein level of PRA(P <0.05) and 0.6 g/kg KTC increased the protein level of PRB in the uteri(P < 0.05). VEGF was highly expressed after treatment with 0.24 and 0.6 g/kg KTC,and Ki-67 was markedly reduced in ovariectomized rats treated with 1.5 g/kg KTC. No difference was found in the expression of PCNA. KTC 0.24 and0.6 g/kg promoted endometrial transformation in immature rabbit uteri.CONCLUSION: KTC does not demonstrate obvious estrogen-like effect on uteri after ovariectomy, but it does exhibit weak progestogen-like effect, by which mechanism of action is yet to be further investigated.
基金supported by National Science Foundation of China(Nos.22106098,21906099,and 22036005)Youth Science and Technology Research Foundation of Shanxi Province(20210302124298)+2 种基金Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi(2020L0174)Startup Foundation for Doctors of Shanxi Province(SD1917)Startup Foundation for Doctors of Shanxi Medical University(XD1917).
文摘Breast cancer incidence has increased and become the world’s most prevalent cancer,which is related to abnormal development of mammary glands and thought to be influenced by environment endocrine disruptors such as bisphenol A(BPA).However,whether its substitution,bisphenol B(BPB),has similar effects remains a concern.In the present study,a maternal exposure model of ICR mice combined time-series RNA-seq analysis was established to explore the underlying correlation among maternal BPB exposure(300μg/kg body weight),mammary gland development,and long-term breast health in offspring.The results showed that BPB exposure disrupted hormonal homeostasis of the female offspring but did not affect the branch development of mammary glands in a time-dependent manner.However,at postnatal day 90(PND90),BPB exposure resulted in duct dilatation,lobular hyperplasia,and inflammatory cell infiltration and increased the number of hormone receptor-expressing(HR+)luminal cells in offspring.Further,the differentially expressed genes in time-series analysis of RNA-seq for mammary glands of the female offspring were enriched in the morphogenesis of branching structures,branching epithelium,and branching morphogenesis of epithelial tubes,which are always considered gland development.Interestingly,the results of RNA-seq also suggested that progesterone receptor(Pgr)mRNA expression in the BPB group was elevated at PND90,and breast cancer related genes such as GATA binding protein 3(Gata3)and epidermal growth factor receptor(Egfr)were also altered.These findings suggested that maternal BPB exposure did not accelerate mammary gland development or lead to obvious morphological anomalies of offspring,but it induced pathological changes and altered cancer related gene expression in adult offspring breast.
