Homo sapiens
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PROVIDER: PRJNA122265 | ENA |
REPOSITORIES: ENA
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Project description:High doses of genistein show an inhibitory effect on uterine leiomyoma (UtLM) cell proliferation. Using microarray analysis and Ingenuity Pathways AnalysisTM, we identified genes (up- or down-regulated, ≥1.5 fold, P ≤ 0.001), functions and signaling pathways that were altered following treatment with an inhibitory concentration of genistein (50 ìg/ml) in UtLM cells. Downregulation of TGF-â signaling pathway genes, activin A, activin B, Smad3, TGF-â2 and genes related to cell cycle regulation, with the exception of the upregulation of the CDK inhibitor P15, were identified and validated by real-time reverse transcriptase-polymerase chain reaction studies. Western blot analysis further demonstrated decreased protein expression of activin A and Smad3 in genistein-treated UtLM cells. Moreover, we found that activin A stimulated the growth of UtLM cells, and the inhibitory effect of genistein was partially abrogated in the presence of activin A. Overexpression of activin A and Smad3 were found in tissue samples of leiomyoma compared to matched myometrium, supporting the contribution of activin A and Smad3 in promoting the growth of UtLM cells. Taken together, these results suggest that downregulation of activin A and Smad3, both members of the TGF-â pathway, may offer a mechanistic explanation for the inhibitory effect of a high-dose of genistein on UtLM cells, and might be potential therapeutic targets for treatment of clinical cases of uterine leiomyomas.
2012-05-01 | GSE19477 | GEO
Project description:High doses of genistein show an inhibitory effect on uterine leiomyoma (UtLM) cell proliferation. Using microarray analysis and Ingenuity Pathways AnalysisTM, we identified genes (up- or down-regulated, M-bM-^IM-%1.5 fold, P M-bM-^IM-$ 0.001), functions and signaling pathways that were altered following treatment with an inhibitory concentration of genistein (50 M-CM-,g/ml) in UtLM cells. Downregulation of TGF-M-CM-" signaling pathway genes, activin A, activin B, Smad3, TGF-M-CM-"2 and genes related to cell cycle regulation, with the exception of the upregulation of the CDK inhibitor P15, were identified and validated by real-time reverse transcriptase-polymerase chain reaction studies. Western blot analysis further demonstrated decreased protein expression of activin A and Smad3 in genistein-treated UtLM cells. Moreover, we found that activin A stimulated the growth of UtLM cells, and the inhibitory effect of genistein was partially abrogated in the presence of activin A. Overexpression of activin A and Smad3 were found in tissue samples of leiomyoma compared to matched myometrium, supporting the contribution of activin A and Smad3 in promoting the growth of UtLM cells. Taken together, these results suggest that downregulation of activin A and Smad3, both members of the TGF-M-CM-" pathway, may offer a mechanistic explanation for the inhibitory effect of a high-dose of genistein on UtLM cells, and might be potential therapeutic targets for treatment of clinical cases of uterine leiomyomas. Cells were treated with either genistein (50 M-NM-<g/ml) (4M-bM-^@M-^Y, 5, 7-Trihydroxyisoflavone; Sigma Chemical Company, St. Louis, MO, USA) or the vehicle control [0.3% dimethylsulfoxide (DMSO), Sigma] for 24 h. the samples from the flasks that received the same treatment were pooled, then concentrated to > 9 M-CM-,g/M-CM-,l by Microcon 30 columns (Amicon:Millipore, Bedford, MA, USA). Three replicates for the treatment, and one pooled control, were submitted for microarray analysis. Gene expression analysis was conducted using Agilent Whole Human Genome arrays (Agilent Technologies, Palo Alto, CA, USA).
2012-04-30 | E-GEOD-19477 | biostudies-arrayexpress
Project description:Purpose:Our goal was to identify and characterize a new molecular target of Bisphenol A（BPA）in uterine leiomyoma cells to better understand how this compound may affect uterine leiomyomas growth and development. Methods: Primary cultured cell lines of uterine leiomyoma were treated with 0.1% DMSO or 10.0 μmol/L BPA for 48 h before RNA-seq and histone 3 lysine 27 acetylation (H3K27ac) ChIP-seq were performed. Integrative analysis of ChIP-seq and RNA-seq data identifies the key transcription factor (TF)，target gene and signaling pathway. To confirm the expression level of TF and target gene in uterine leiomyomas tissues, we analyzed 10 human uterine leiomyoma tissues and the matched adjacent uterine smooth muscle tissues using western blotting, and 96 paired paraffin-embedded human uterine samples by immunohistochemistry(IHC). The ChIP assay used to confirm the combination between the TF and target gene. In order to verify the functions of key TF, lentivirus was used to knock down the expression level and detect the effects on cell proliferation, cell cycle, and cell tumorigenicity. We further conducted Western blot analysis to confirm the whether the downstream signaling pathway is activated. RESULTS: Integrative Analysis of ChIP-seq and RNA-seq data identifies the key transcription factor XBP1and target gene ITGA2. The qPCR and ChIP- qPCR initially verified the sequencing results. XBP1 and ITGA2 were overexpressed in human uterine leiomyoma tissues. The IHC results confirmed that ITGA2 was significantly correlated with XBP1 expression (R = 0.6708, P < 0.001)， and the ChIP assay showed that XBP1 binds to the the ITGA2 predicted promoter region. BPA promoted uterine leiomyoma cells proliferation both in vitro and in vivo and that XBP1 expression levels modulated the cellular response to this endocrine disruptor. BPA upregulated ITGA2 through XBP1 and activated the downstream PI3K-AKT signaling pathway to promote the proliferation of human uterine leiomyoma cells. CONCLUSION: In conclusion, our current work reveals a novel mechanism by which BPA promotes the proliferation in uterine leiomyoma cells. The XBP1 transcription factor regulates and activates the downstream ITGA2/PI3K/AKT pathway. By defining XBP1 as an important regulatory role of BPA in uterine leiomyoma cell proliferation, they provide new insights into the pathogenesis related to the exposure to BPA and other endocrine disruptors acting similarly, and XBP1 may serve as a candidate molecular target for intervention and treatment of uterine leiomyomas.
2021-08-20 | GSE182469 | GEO
Project description:Uterine leiomyomata, or fibroids, are benign tumors of the uterine myometrium that significantly affect up to 30% of reproductive-age women. Despite being the primary cause of hysterectomy in the United States, accounting for up to 200,000 procedures annually, the etiology of leiomyoma remains largely unknown. Due to the lack of an effective medicinal therapy for these tumors, this disease continues to have a tremendous negative impact on women’s health. As a basis for understanding leiomyoma pathogenesis and identifying targets for pharmacotherapy, we conducted transcriptional profiling of leiomyoma and unaffected myometrium from humans and Eker rats, the best characterized preclinical model of leiomyoma. A global comparison of mRNA from leiomyoma versus myometrium in human and rat identified a highly significant overlap of dysregulated gene expression in leiomyoma. An unbiased pathway analysis using a method of gene set enrichment based on the Sigpathway algorithm detected the mammalian target of rapamycin (mTOR) pathway as one of the most highly upregulated pathways in both human and rat tumors. Activation of this pathway was confirmed in both human and rat leiomyomata at the protein level via Western. Inhibition of mTOR in female Eker rats with the rapamycin analog WAY-129327 for 2 weeks decreased mTOR signaling and cell proliferation in tumors, and treatment for 4 months significantly decreased tumor incidence, multiplicity and size. These results identify dysregulated mTOR signaling as a component of leiomyoma etiology across species and directly demonstrate the dependence of these tumors on mTOR signaling for growth in the Eker rat. Modulation of this pathway warrants additional investigation as a potential therapy for uterine leiomyoma. Experiment Overall Design: We analyzed 1-3 leiomyoma or normal myometrium biopsies from each 23 woman undergoing hysterectomy for the treatment of uterine fibroids. tment and compared it leiomyoma and normal myometrium from the Eker rat model of uterine fibroids (N=14-15)
2009-09-05 | E-GEOD-13319 | biostudies-arrayexpress
Project description:Global protein coding gene and miRNA expression profiling studies in uterine leiomyoma showed their aberrant expression and involvement in the pathogenesis of uterine leiomyoma. But the global expression patterns and potential clinical value of long noncoding RNA (lncRNA) in uterine leiomyoma have not been explored.In this study, we performed lncRNA expression profiles analysis of uterine leiomyoma using microarray(Arraystar Human LncRNA Array v2.0) to evaluate the genome-wide expression of lncRNAs and mRNAs and their potential role in the pathogenesis of uterine leiomyoma.
2014-08-14 | GSE52618 | GEO
Project description:Transcriptional profiling of uterine leiomyoma tumor samples for integrative analysis with copy number alterations data. Goal was to identify up- and/or down-expressed genes associated with genomic gains and/or losses, respectively. After, it was applied to GSEA and CONEXIC algorithm to integrate the data. Protein-protein interactions also was building and the data were validated using qRT-PCR and IHC techniques. Experiment condition, 51 uterine leiomyoma samples from patients at the secretory or proliferative menstrual cycle phases were labeled with Cy3 and adjacent normal myometrium reference samples were labeled with Cy5. Each uterine leiomyoma and adjacent normal myometrium sample were obtained from the same patient and were mixed and hybridized on a glass slide Agilent 4x44 platform.
2012-12-16 | E-GEOD-42939 | biostudies-arrayexpress
Project description:Global protein coding gene and miRNA expression profiling studies in uterine leiomyoma showed their aberrant expression and involvement in the pathogenesis of uterine leiomyoma. But the global expression patterns and potential clinical value of long noncoding RNA (lncRNA) in uterine leiomyoma have not been explored.In this study, we performed lncRNA expression profiles analysis of uterine leiomyoma using microarray(Arraystar Human LncRNA Array v2.0) to evaluate the genome-wide expression of lncRNAs and mRNAs and their potential role in the pathogenesis of uterine leiomyoma. Expression profiling analysis of the 15 samples including 5 large fibroids, 5 small fibroids and 5 matched myometrium by Arraystar Human LncRNA Array v2.0.
2014-08-14 | E-GEOD-52618 | biostudies-arrayexpress
Project description:Epidemiological data indicate that consumption of soy-based food significantly reduces the cancer risk in human through interaction with estrogen receptors and the ‘phytoestrogen’ genistein present in the soy is responsible for this chemopreventive activity. The epigenome regulatory effect of genistein also reported but the key mechanism behind this effect remain elusive. In this current project, we reported the epigenome modulation effect of genistein using MDA-MB231 cells. Cells were treated with low-dose genistein for >1 month and the stable epigenetic alterations were analyzed by partial MNase digestion and TMT-based quantitative proteomics based chromatome mapping approach. We identified a total of 3177 chromatin-bound proteins with high confidence, including 882 proteins that displayed altered binding topology after cell conditioning with genistein. Prolonged phytochemical exposure permanently modified the binding topology of the key epigenetic regulators and preserved their binding topology in untreated progeny. Genistein induced altered epigenome modulation negatively regulates the expression of cell proliferation genes and suppress cell growth. In contrast, previously exposed cells displayed reduced expression of DNA repair genes and enhanced genotoxic stress upon genistein withdrawal.
2018-07-05 | PXD006178 | Pride
Project description:Uterine leiomyomata, or fibroids, are benign tumors of the uterine myometrium that significantly affect up to 30% of reproductive-age women. Despite being the primary cause of hysterectomy in the United States, accounting for up to 200,000 procedures annually, the etiology of leiomyoma remains largely unknown. Due to the lack of an effective medicinal therapy for these tumors, this disease continues to have a tremendous negative impact on women’s health. As a basis for understanding leiomyoma pathogenesis and identifying targets for pharmacotherapy, we conducted transcriptional profiling of leiomyoma and unaffected myometrium from humans and Eker rats, the best characterized preclinical model of leiomyoma. A global comparison of mRNA from leiomyoma versus myometrium in human and rat identified a highly significant overlap of dysregulated gene expression in leiomyoma. An unbiased pathway analysis using a method of gene set enrichment based on the Sigpathway algorithm detected the mammalian target of rapamycin (mTOR) pathway as one of the most highly upregulated pathways in both human and rat tumors. Activation of this pathway was confirmed in both human and rat leiomyomata at the protein level via Western. Inhibition of mTOR in female Eker rats with the rapamycin analog WAY-129327 for 2 weeks decreased mTOR signaling and cell proliferation in tumors, and treatment for 4 months significantly decreased tumor incidence, multiplicity and size. These results identify dysregulated mTOR signaling as a component of leiomyoma etiology across species and directly demonstrate the dependence of these tumors on mTOR signaling for growth in the Eker rat. Modulation of this pathway warrants additional investigation as a potential therapy for uterine leiomyoma. Keywords: Disease State Analysis: Animal Model Validation
2009-08-20 | GSE13319 | GEO
Project description:Purpose:The study aimed to recognize potential molecular targets and signal pathways whereby phenolic environmental estrogen promotes the proliferation of uterine leiomyoma cells Methods:Primary cultured cell lines were treated with 0.1% DMSO, 10.0 μmol/L BPA, and 32.0 μmol/L NP for 48 h before RNA-seq was performed. Differentially expressed genes affected by BPA and NP were selected. Then, Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and Protein-protein Interaction (PPI) analysis were performed. Quantitative real-time polymerase chain reaction (q-PCR) was used to verify the differentially expressed genes Results:In comparison with the control group, 739 differentially expressed mRNAs were identified in the BPA intervention group and the NP intervention group. GO enrichment analysis results show that the most enriched GO terms were connective tissue development and G1/S transition of mitotic cell cycle, and extracellular matrix. The results of KEGG enrichment analysis showed that differentially expressed mRNA was enriched mainly in three primary pathways, including environmental information processing, human diseases, and cellular processes. The cell cycle, PI3K-Akt signaling pathway, pathways in cancer, and TGF-beta signaling pathway are significantly enriched. Conclusions:Phenolic environmental estrogens may promote the proliferation and cell cycle progression of uterine leiomyoma cells through rapid non-genomic ER signaling, which leads to disordered cell cycle regulation and accelerates the transition of the cell cycle from G0/G1 phase to S phase. In addition, as an external harmful stimulant, phenolic estrogen promotes the upregulation of inflammatory factors in uterine leiomyomas.
2021-04-27 | GSE173334 | GEO