Effects of the treatment of osteomodulin on gene expression in cultured human primary trabecular osteoblasts
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE230198 | GEO | 2023/04/26
REPOSITORIES: GEO
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Project description:Metabolism of anticancer drugs markedly affects their antitumor effects. The major goal of our study was to investigate associations of gene expression of enzymes metabolizing taxanes and/or anthracyclines with therapy response and survival of breast carcinoma patients AKR1A1 was significantly overexpressed and AKR1C1-4, KCNAB1, CYP2C19, CYP3A4, and CYP3A5 downregulated in tumors compared with control non-neoplastic tissues after correction for multiple testing. Significant associations of CYP2B6 levels in tumors with expression of hormonal receptors were found. Significantly higher intratumoral levels of AKR1C1, AKR1C2, and CYP2W1 were found in responders to NACT compared with non-responders. Patients with high AKR1C2 and CYP3A4 levels had significantly longer disease-free survival than patients with low levels. Transcript levels of twenty-four selected human metabolic genes (CYPs and AKRs) were determined by qPCR in post-treatment tumor and non-neoplastic tissue samples from 68 breast carcinoma patients treated by anthracycline and/or taxane based neoadjuvant chemotherapy. EIF2B1, MRPL19, IPO8, and UBB were used as reference genes for data normalization.
2014-08-31 | E-GEOD-56259 | biostudies-arrayexpress
Project description:Metabolism of anticancer drugs markedly affects their antitumor effects. The major goal of our study was to investigate associations of gene expression of enzymes metabolizing taxanes and/or anthracyclines with therapy response and survival of breast carcinoma patients AKR1A1 was significantly overexpressed and AKR1C1-4, KCNAB1, CYP2C19, CYP3A4, and CYP3A5 downregulated in tumors compared with control non-neoplastic tissues after correction for multiple testing. Significant associations of CYP2B6 levels in tumors with expression of hormonal receptors were found. Significantly higher intratumoral levels of AKR1C1, AKR1C2, and CYP2W1 were found in responders to NACT compared with non-responders. Patients with high AKR1C2 and CYP3A4 levels had significantly longer disease-free survival than patients with low levels.
2014-08-31 | GSE56259 | GEO
Project description:Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, is a potent inhibitor of experimental mammary carcinogenesis and may be an effective, safe chemopreventive agent for use in humans. SFN acts in part on the Keap1/Nrf2 pathway to regulate a battery of cytoprotective genes. In this study transcriptomic and proteomic changes in the estrogen receptor negative, non tumorigenic human breast epithelial MCF10A cell line were analyzed following SFN treatment or KEAP1 knockdown with siRNA using microarray and stable isotopic labeling with amino acids in culture (SILAC), respectively. Changes in selected transcripts and proteins were confirmed by PCR and Western blot in MCF10A and MCF12A cells. There was strong correlation between the transcriptomic and proteomic responses in both the SFN treatment (R=0.679, P<0.05) and KEAP1 knockdown (R=0.853, P<0.05) experiments. Common pathways for SFN treatment and KEAP1 knockdown were xenobiotic metabolism and antioxidants, glutathione metabolism, carbohydrate metabolism and NADH/NADPH regeneration. Moreover, these pathways were most prominent in both the transcriptomic and proteomic analyses. The aldo-keto reductase family members, AKR1B10, AKR1C1, AKR1C2 and AKR1C3, as well as NQO1 and ALDH3A1, were highly upregulated at both the transcriptomic and proteomic level. Collectively, these studies served to identify potential biomarkers that can be used in clinical trials to investigate the initial pharmacodynamic action of SFN in the breast. MCF10A cells were treated with SFN or had KEAP1 knocked down by siRNA.
2011-04-22 | E-GEOD-28813 | biostudies-arrayexpress
Project description:This is the first study to demonstrate that co-treatment with MLT and oTR has a synergistic effect in inhibiting the proliferation of MDA-MB-231/RR cells based on metabolic and transcriptomic analyses. Treatment with either 1 mM MLT or 1 μM oTR was not cytotoxic, while their synergistic activity upon co-treatment was cytotoxic. In our previous study, MDA-MB-231 cells acquired radio resistance as mitochondrial respiration increased; however, co-treatment with MLT and oTR simultaneously inhibited mitochondrial respiration and glycolysis. Furthermore, when integrating the transcriptomic and metabolic profile results, alteration of pyrimidine metabolism (aspartate, uracil, CDA, NME1), steroid hormone biosynthesis (AKR1C1, AKR1C2, AKR1C3), and Wnt/β-catenin signaling (TSNAX-DISC1, CYP1B1) was attributed to the synergistic cytotoxicity by the co-treatment. In future studies, proteomic profiling could be performed to verify the results of the metabolomic and transcriptomic profiling in this study. The results of this study should be validated with in vivo experiment as a prelude to future clinical trials for the treatment of radioresistant TNBC. We expect our findings to provide basic information for the treatment of radioresistant TNBC.
2024-10-10 | GSE279115 | GEO
Project description:Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, is a potent inhibitor of experimental mammary carcinogenesis and may be an effective, safe chemopreventive agent for use in humans. SFN acts in part on the Keap1/Nrf2 pathway to regulate a battery of cytoprotective genes. In this study transcriptomic and proteomic changes in the estrogen receptor negative, non tumorigenic human breast epithelial MCF10A cell line were analyzed following SFN treatment or KEAP1 knockdown with siRNA using microarray and stable isotopic labeling with amino acids in culture (SILAC), respectively. Changes in selected transcripts and proteins were confirmed by PCR and Western blot in MCF10A and MCF12A cells. There was strong correlation between the transcriptomic and proteomic responses in both the SFN treatment (R=0.679, P<0.05) and KEAP1 knockdown (R=0.853, P<0.05) experiments. Common pathways for SFN treatment and KEAP1 knockdown were xenobiotic metabolism and antioxidants, glutathione metabolism, carbohydrate metabolism and NADH/NADPH regeneration. Moreover, these pathways were most prominent in both the transcriptomic and proteomic analyses. The aldo-keto reductase family members, AKR1B10, AKR1C1, AKR1C2 and AKR1C3, as well as NQO1 and ALDH3A1, were highly upregulated at both the transcriptomic and proteomic level. Collectively, these studies served to identify potential biomarkers that can be used in clinical trials to investigate the initial pharmacodynamic action of SFN in the breast.
2011-04-22 | GSE28813 | GEO
Project description:Transcriptional activity was identified in all categories of genes expressed by ADSC, including collagens, ECM and basement membrane constituents, adhesion molecules involved in cell-cell and cell-matrix interactions, and proteases involved in degradation of the ECM and their inhibitors. Importantly, it was observed that ADSC synthesize and secrete all three collagen VI chains, suggesting suitability of ADSC for collagen VI congenital muscular dytrophy treatment. We developed a procedure for isolation of human stem cells from adipose layer of neonatal foreskin skin. The adipose-derived stem cells (ADSC) were examined for expression of extracellular matrix (ECM) and related genes using gene expression array analysis.
2013-09-21 | E-GEOD-51030 | biostudies-arrayexpress
Project description:Purpose: Nucleotide excision repair (NER) in mammalian cells requires the xeroderma pigmentosum group A protein (XPA) as a core factor. Remarkably, XPA and other NER proteins have been detected by chromatin immunoprecipitation at some active promoters, and NER deficiency is reported to influence the activated transcription of selected genes. However, the global influence of XPA on transcription in human cells has not been determined. Methods: We analyzed the human transcriptome by RNA sequencing (RNA-Seq). Four genetically matched human cell line pairs deficient or proficient in XPA were analyzed Results: Of the ~14,000 genes transcribed in each cell line, 325 genes (2%) had a significant XPA-dependent directional change in gene expression that was common to all four pairs (with a false discovery rate of 0.05). These genes were enriched in pathways for the maintenance of mitochondria. Only 27 genes were different by more than 1.5-fold. The most significant hits were AKR1C1 and AKR1C2, involved in steroid hormone metabolism. AKR1C2 protein was lower in all of the immortalized XPA-deficient cells. Retinoic acid treatment led to modest XPA-dependent activation of some genes with transcription-related functions. Conclusions: We conclude that XPA status does not globally influence human gene transcription. However, XPA significantly influences expression of a small subset of genes important for mitochondrial functions and steroid hormone metabolism. The results may help explain defects in neurological function and sterility in individuals with xeroderma pigmentosum.
2017-07-07 | GSE100855 | GEO
Project description:Background: Aldo-keto reductase (AKR) 1C family member 3 (AKR1C3), one of four identified human AKR enzymes, catalyzes steroid, prostaglandin, and xenobiotic metabolism. In the prostate, AKR1C3 is up-regulated in localized and advanced prostate adenocarcinoma, and is associated with prostate cancer (PCa) aggressiveness. Here we provide initial evidence for potential roles of AKR1C3 in PCa progression. Methods: Spatial distribution of AKR1C3 was analyzed using immunohistochemical staining in prostate adenocarcinoma tissue array. Human PCa PC-3 cells were stably transfected with AKR1C3 cDNA to establish PC3-AKR1C3 transfectants. Microarray and bioinformatics analyses were performed to identify pathways that are activated by elevated AKR1C3 expression in PCa cells. Functional confirmation of microarray and bioinformatics results was performed by immunoblot analysis and an in vitro Matrigel angiogenesis assay. Results: Elevated AKR1C3 expression was specifically limited to human prostate adenocarcinoma. Microarray and bioinformatics analysis suggested that elevated AKR1C3 expression in PC-3 cells modulates estradiol and androgen metabolism and activates insulin growth factor (IGF)-1 and Akt signaling pathways. Immunoblots confirmed that phosphorylated levels of IGF-1 receptor (IGF-1R) and Akt are significantly up-regulated in PC3-AKR1C3 as compared to mock transfectants. PC3-AKR1C3 transfectants promoted endothelial cell tube formation in Matrigel as compared to parental PC-3 cells and mock transfectants. Conclusion: Microarray and bioinformatics data followed by biological analyses suggest that elevated AKR1C3 expression in PC-3 cells promotes PCa angiogenesis and aggressiveness. These results suggest AKR1C3 can promote the aggressiveness of PCa through modulating estrogen and androgen metabolism with subsequent activation of growth factor IGF-1 and cytoplasmic Akt signaling pathways.
2010-08-10 | GSE20956 | GEO
Project description:The abstract of the associated publication (Selga E, Noé V, Ciudad CJ. Biochemical Pharmacology 2007 Sep 8; Article in press) is the following:; While studying differentially expressed genes between sensitive and 10-5 M Methotrexate (MTX) resistant HT29 human colon cancer cells, we identified some members of the aldo-keto reductase (AKR) superfamily. The study was followed with the member AKR1C1 (EC 1.1.1.213), validating its increase in mRNA and protein levels in MTX resistant cells. The genomic content for AKR1C1 remained unchanged between sensitive and resistant cells, thereby excluding a mechanism of AKR1C1 gene amplification. Thus, we cloned the AKR1C1 human promoter and performed luciferase experiments that revealed a transcriptional regulation of the gene in the resistant cells. Computational studies showed a putative binding site for the transcription factor Sp1. The co-transfection of Sp1 or Sp3 with different constructs of AKR1C1 promoter deletions, including and excluding the proximal GC-box, demonstrated a key role for these factors in regulating AKR1C1 transcriptional activity. Gel-shift assays revealed an increase in Sp1 and Sp3 binding in resistant compared to sensitive cells, without differences in Sp1 protein levels. Dephosphorylation of the extracts coincided with a decrease in Sp1 binding, which is consistent with a process of regulation of Sp1 by phosphorylation. We also investigated the possible relationship between AKR1C1 expression and MTX action. Overexpression of AKR1C1 counteracted the S-phase accumulation of cells and apoptosis caused by MTX treatment. This suggests a role of AKR1C1 in cell proliferation. Finally, overexpression of AKR1C1 in MTX sensitive HT29 cells conferred resistance to the chemotherapeutic agent and silencing of AKR1C1 by means of iRNA technology sensitized the cells to MTX. Experiment Overall Design: Two cell lines are compared in the study, which are HT29 colon cancer cells sensitive to methotrexate and HT29 cells resistant to 10e-5M methotrexate. Six samples are provided, which correspond to triplicates of each cell line. The samples provided were subsequently normalyzed and analyzed using the specific software GeneSpring GX 7.3.1
2008-06-16 | E-GEOD-9412 | biostudies-arrayexpress
Project description:In this study, Genome-wide transcriptomes of CD8+ T cells from HCV/HIV co-infected or mono-infected treatment-naive individuals were analyzed by using microarray assays. Pairwise comparisons were performed and differentially expressed genes were identified followed by quantitative real time PCR (qRT-PCR) validation. To identify the important functional categories, Directed Acyclic Graphs (DAG) from Web-based Gene SeT AnaLysis Toolkit (WebGestalt) was used to find out Gene Ontology (GO) categories with significantly enriched gene numbers. The enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were also obtained by using the similar methods in the same website.
2012-05-17 | E-MEXP-3635 | biostudies-arrayexpress