Quinoline compounds treated bladder cancer for proteomics sequencing
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Yong Xia
PROVIDER: PXD079203 | iProX | Wed Jun 03 00:00:00 BST 2026
REPOSITORIES: iProX
Similar Datasets
Project description:Here we report the discovery of truncating mutations of the gene encoding the cohesin subunit STAG2, which regulates sister chromatid cohesion and segregation, in 36% of papillary non-invasive urothelial carcinomas and 16% of invasive urothelial carcinomas of the bladder. Our studies suggest that STAG2 has a role in controlling chromosome number but not the proliferation of bladder cancer cells. These findings identify STAG2 as one of the most commonly mutated genes in bladder cancer. Affymetrix CytoScan HD Arrays were performed according to the manufacturer's directions on genomic DNA extracted directly from 12 snap-frozen human urothelial carcinoma primary tumors with somatic mutations of the STAG2 gene.
2013-06-30 | GSE41581 | GEO
Project description:PURPOSE: Despite over 70,000 new cases of bladder cancer in the United States annually, patients with advanced disease have a poor prognosis due to limited treatment modalities. We evaluate the role of Aurora A, identified as an upregulated candidate molecule in bladder cancer, in regulating bladder tumor growth. EXPERIMENTAL DESIGN: Gene expression in human bladder cancer samples was evaluated using RNA microarray and reverse-transcriptase PCR. The specific Aurora kinase A inhibitor MLN8237 (Millennium) was used to determine effects on bladder cancer cell growth using in vitro and in vivo models using malignant T24 and UM-UC-3 and papilloma-derived RT4 bladder cells. RESULTS: Urothelial carcinoma upregulates a set of 13 mitotic spindle associated transcripts, as compared to normal urothelium, including MAD2L1 (7.6-fold), BUB1B (8.8-fold), Aurora kinases A (5.6-fold) and Aurora kinase B (6.2-fold). Application of MLN8237 (10nM-1µM) to the human bladder tumor cell lines T24 and UM-UC-3 induced dose-dependent G2 cell cycle arrest, aneuploidy, mitotic spindle abnormalities, and apoptosis. MLN8237 arrested tumor growth when administered orally over 4 weeks in a mouse bladder cancer xenograft model (p<0.05). Finally, in vitro combination of MLN8237 with either paclitaxel or gemcitabine produced schedule-dependent synergistic antiproliferative effects in T24 cells when administered sequentially. CONCLUSIONS: Mitotic spindle checkpoint dysfunction is a common characteristic of human urothelial carcinoma, and can be exploited with pharmacologic Aurora A inhibition. Future studies that explore the mechanisms of spindle checkpoint failure in bladder cancer and evaluate the therapeutic role of Aurora kinases for bladder cancer patients would be of value. Tissue samples with urothelial cell carcinoma from bladder as well as normal references were collected and the gene expression profiles were compared. No technical replicates.
2013-05-01 | E-GEOD-42089 | biostudies-arrayexpress
Project description:PURPOSE: Despite over 70,000 new cases of bladder cancer in the United States annually, patients with advanced disease have a poor prognosis due to limited treatment modalities. We evaluate the role of Aurora A, identified as an upregulated candidate molecule in bladder cancer, in regulating bladder tumor growth. EXPERIMENTAL DESIGN: Gene expression in human bladder cancer samples was evaluated using RNA microarray and reverse-transcriptase PCR. The specific Aurora kinase A inhibitor MLN8237 (Millennium) was used to determine effects on bladder cancer cell growth using in vitro and in vivo models using malignant T24 and UM-UC-3 and papilloma-derived RT4 bladder cells. RESULTS: Urothelial carcinoma upregulates a set of 13 mitotic spindle associated transcripts, as compared to normal urothelium, including MAD2L1 (7.6-fold), BUB1B (8.8-fold), Aurora kinases A (5.6-fold) and Aurora kinase B (6.2-fold). Application of MLN8237 (10nM-1µM) to the human bladder tumor cell lines T24 and UM-UC-3 induced dose-dependent G2 cell cycle arrest, aneuploidy, mitotic spindle abnormalities, and apoptosis. MLN8237 arrested tumor growth when administered orally over 4 weeks in a mouse bladder cancer xenograft model (p<0.05). Finally, in vitro combination of MLN8237 with either paclitaxel or gemcitabine produced schedule-dependent synergistic antiproliferative effects in T24 cells when administered sequentially. CONCLUSIONS: Mitotic spindle checkpoint dysfunction is a common characteristic of human urothelial carcinoma, and can be exploited with pharmacologic Aurora A inhibition. Future studies that explore the mechanisms of spindle checkpoint failure in bladder cancer and evaluate the therapeutic role of Aurora kinases for bladder cancer patients would be of value.
2013-05-01 | GSE42089 | GEO
Project description:Bladder cancer is one of the most common genitourinary malignancies worldwide. It is a heterogeneous disease at the clinical, pathological, and genetic levels. In an exome-sequencing study of bladder cancer, we identified genes mutated in bladder cancer coding for proteins involved in chromatin modification, cell division, and DNA repair. STAG2, a constituent of the cohesin complex, was commonly mutated or lost, mainly in tumors of low stage or grade. Loss of STAG2 expression was often observed in genomically stable tumors, suggesting that STAG2 may act as a tumor suppressor through mechanisms other than chromosome segregation (Balbás-Martínez et al. 2013). In addition to mediating sister chromatid cohesion, cohesin plays a central role in DNA looping and organization of the genome into Topologically Associating Domains (TADs). Two variant cohesin complexes that contain either STAG1 or STAG2 are present in all cell type. Here we addressed their genome wide binding in bladder cancer cells.
2021-03-15 | GSE111913 | GEO
Project description:Heritable genetic changes continually arise in cancer, especially in solid tumors where cells sometimes appear compressed. Rare heritable losses of chromosomes in live cells are quantified here with chromosome reporters (ChReporters) that show similar losses after mild or strong compression. Mild compression (to <40% of interphase height) perturbs mitotic spindles and prolongs pro/metaphase but ruptures few nuclei compared to strong compression. Unexpectedly, chromosome mis-segregation into micronuclei emerges only after release from mild confinement, but arrest and death predominate. All such effects are phenocopied by Nocodazole washout that induces a ‘memory’ of prolonged mitosis. The results differ from transient inhibition of the spindle assembly checkpoint and cell cycle entry with a CDK4/6-inhibitor – both of which quickly generate micronuclei. Single-cell-RNA-sequencing confirms chromosome loss days after confinement and reveals persistent upregulation of chromosome segregation. The results suggest a mitotic memory of confinement, addressing a significant gap in mechanobiology and cancer evolution.
2026-01-28 | GSE317816 | GEO
Project description:Here we apply single cell bisulfite sequencing to detect epigenetic and genetic changes that occur in BRAF V600E cells that escape G1 arrest and return to the cell cycle during treatment with the MEK inhibitor selumetinib. We detect no major changes in DNA methylation, but find that cells in G2 are enriched in large amplifications and deletions that we ascribe to abnormal mitotic chromosome segregation.
2022-09-11 | GSE212899 | GEO
Project description:During mitosis, the genome is restructured to facilitate chromosome segregation, accompanied by dramatic changes in gene expression. However, the mechanisms that underlie mitotic transcriptional regulation are unclear. In contrast to transcribed genes, centromere regions retain transcriptionally active RNA Polymerase II (RNAPII) in mitosis. Here, we demonstrate that chromosome-localized cohesin is necessary and sufficient to retain active RNAPII on mitotic centromeres. Failure to remove cohesin from mitotic chromosome arms dramatically alters mitotic gene expression, and results in a failure to release elongating RNAPII and nascent transcripts from mitotic chromosomes. We propose that prophase cohesin removal is the key step in reprogramming gene expression as cells transition from G2 to mitosis, and is temporally coupled with chromosome condensation to coordinate chromosome segregation with changes in gene expression.
2020-01-30 | GSE139846 | GEO
Project description:During mitosis, the genome is restructured to facilitate chromosome segregation, accompanied by dramatic changes in gene expression. However, the mechanisms that underlie mitotic transcriptional regulation are unclear. In contrast to transcribed genes, centromere regions retain transcriptionally active RNA Polymerase II (RNAPII) in mitosis. Here, we demonstrate that chromosome-localized cohesin is necessary and sufficient to retain active RNAPII on mitotic centromeres. Failure to remove cohesin from mitotic chromosome arms dramatically alters mitotic gene expression, and results in a failure to release elongating RNAPII and nascent transcripts from mitotic chromosomes. We propose that prophase cohesin removal is the key step in reprogramming gene expression as cells transition from G2 to mitosis, and is temporally coupled with chromosome condensation to coordinate chromosome segregation with changes in gene expression.
2020-01-30 | GSE139845 | GEO
Project description:During mitosis, the genome is restructured to facilitate chromosome segregation, accompanied by dramatic changes in gene expression. However, the mechanisms that underlie mitotic transcriptional regulation are unclear. In contrast to transcribed genes, centromere regions retain transcriptionally active RNA Polymerase II (RNAPII) in mitosis. Here, we demonstrate that chromosome-localized cohesin is necessary and sufficient to retain active RNAPII on mitotic centromeres. Failure to remove cohesin from mitotic chromosome arms dramatically alters mitotic gene expression, and results in a failure to release elongating RNAPII and nascent transcripts from mitotic chromosomes. We propose that prophase cohesin removal is the key step in reprogramming gene expression as cells transition from G2 to mitosis, and is temporally coupled with chromosome condensation to coordinate chromosome segregation with changes in gene expression.
2020-01-30 | GSE130558 | GEO
Project description:Chemical inhibitors of the deubiquitinase USP7 are currently being developed as anticancer agents, due to their capacity to activate P53. Regardless of this activity, USP7 inhibitors also generate DNA damage in a p53-independent manner. However, the mechanism of this genotoxicity remains unknown. Surprisingly, even if USP7 inhibitors stop DNA replication, this occurs concomitant to a premature activation of mitotic kinases such as CDK1, which impairs chromosome segregation and is toxic for mammalian cells. Mechanistically, we show that USP7 interacts with the phosphatase PP2A and regulates its function. Accordingly, USP7 or PP2A inhibition trigger similar changes on the phosphoproteome, with a particular bias towards mitotic targets. Supporting our model, the toxicity of USP7 inhibitors is alleviated by lowering CDK1 activity or by the chemical activation of PP2A. Our work sheds light into the mechanism of action of USP7 inhibitors and provides the first example of triggering premature mitotic entry through perturbation of ubiquitin signaling.
2021-03-09 | PXD016623 | Pride