Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA200286 | ENA |
REPOSITORIES: ENA
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Project description:In this study we show that lysyl oxidase (LOX), an enzyme involved in maintaining structural integrity of the extracellular matrix, is expressed at low levels in Ewing sarcoma cells and primary tumors and is downregulated by the EWS/FLI1 oncoprotein characteristic of these tumors. Using a doxycycline inducible system to restore LOX expression in an Ewing sarcoma derived cell line, we show that LOX displays tumor suppressor activities. Interestingly, we show that the tumor suppressor activity resides in the propeptide domain of LOX (LOX-PP), an N-terminal domain produced by proteolytic cleavage during the physiological processing of LOX. Finally, we show that LOX-PP inhibits ERK/MAPK signalling pathway, and that many pathways involved in cell cycle progression were significant deregulated by LOX-PP, providing a mechanistic explanation to the cell proliferation inhibition observed upon LOX-PP expression. In summary, our observations indicate that deregulation of the LOX gene participates in Ewing sarcoma development and identify LOX-PP as a new therapeutic target for one of the most aggressive paediatric malignancies. These findings suggest that therapeutic strategies based in the administration of LOX propeptide or functional analogues could be useful in the treatment of this devastating paediatric cancer. A673 cells derived from Ewing sarcoma were genetically enginereed to express LOX-PP upon doxycycline stimulation (72 hours). Three independent experiments from control cells and three independent experiments from A673 cells expressing LOX-PP were done. Gene expression profile in A673 cells expressing LOX-PP vs control cells were compared.
2013-12-31 | E-GEOD-46407 | biostudies-arrayexpress
Project description:In this study we show that lysyl oxidase (LOX), an enzyme involved in maintaining structural integrity of the extracellular matrix, is expressed at low levels in Ewing sarcoma cells and primary tumors and is downregulated by the EWS/FLI1 oncoprotein characteristic of these tumors. Using a doxycycline inducible system to restore LOX expression in an Ewing sarcoma derived cell line, we show that LOX displays tumor suppressor activities. Interestingly, we show that the tumor suppressor activity resides in the propeptide domain of LOX (LOX-PP), an N-terminal domain produced by proteolytic cleavage during the physiological processing of LOX. Finally, we show that LOX-PP inhibits ERK/MAPK signalling pathway, and that many pathways involved in cell cycle progression were significant deregulated by LOX-PP, providing a mechanistic explanation to the cell proliferation inhibition observed upon LOX-PP expression. In summary, our observations indicate that deregulation of the LOX gene participates in Ewing sarcoma development and identify LOX-PP as a new therapeutic target for one of the most aggressive paediatric malignancies. These findings suggest that therapeutic strategies based in the administration of LOX propeptide or functional analogues could be useful in the treatment of this devastating paediatric cancer.
2013-12-31 | GSE46407 | GEO
Project description:Transcriptomic analysis of the well-characterized Ewing sarcoma cell line A673 indicated that one of the genes more strongly upregulated by EWSR1-FLI1 was FEZF1 (FEZ family zinc finger protein 1), a transcriptional repressor involved in brain development and neural cell identity. FEZF1 was highly expressed in Ewing sarcoma cells but not in other bone tumors such as osteosarcoma or chondrosarcoma. FEZF1 promoter contains a large GGAA-microsatellite and the number of GGAA repeats correlated positively with FEZF1 expression levels in Ewing sarcoma cell lines. To characterize the functional role of FEZF1 in Ewing sarcoma we analyzed the effect of FEZF1 knockdown in three Ewing sarcoma cell lines (A673, SKNMC, SKES1). FEZF1 knockdown inhibited clone formation in clonogenic assays and cell proliferation. Finally, we analyzed the FEZF1-dependent expression profile in A673 cells by RNAseq. Interestingly, several neural genes regulated by FEZF1 were concomitantly regulated by EWSR1-FLI1. In summary, FEZF1 is a transcriptional target of EWSR1-FLI1 in Ewing sarcoma cells involved in the regulation of neural-specific genes which could explain, at least in part, the neural-like phenotype observed in several Ewing sarcoma tumors and derived cell lines.
2021-11-22 | GSE184679 | GEO
Project description:Differential expression of gene was analyzed after FLI1 silencing in Ewing Sarcoma cell line A673.
2019-10-01 | GSE135229 | GEO
Project description:Multi-omics study of DBD-a4 helix of EWS::FLI to understand the underlying mechanism of transcriptional regulation in Ewing sarcoma cell line: A673
2024-02-01 | GSE249578 | GEO
Project description:This study looks at the transcriptional profile of LSD2 knockdown in A673 Ewing sarcoma cells.
2019-08-29 | GSE126275 | GEO
Project description:Comparison of gene expression profile of Ewing sarcoma cells which have an exchange of the endogenous EWS/FLI1 to either wild-type or a turnover-deficient mutant EWS/FLI1. Most target genes are saturated as only a few target genes are soly driven by increasing protein amount. The effect of a stable EWS/FLI1 mutant on global gene expression was evaluated in A673 Ewing sarcoma cells.
2016-11-16 | GSE81018 | GEO
Project description:Ewing sarcoma is an aggressive pediatric small round cell tumor that predominantly occurs in bone. Approximately 85% of Ewing sarcomas harbor the EWS/FLI fusion protein, which arises from a chromosomal translocation, t(11:22)(q24:q12). EWS/FLI interacts with numerous lineage-essential transcription factors to maintain mesenchymal progenitors in an undifferentiated state. We previously showed that EWS/FLI binds the osteogenic transcription factor RUNX2 and prevents osteoblast differentiation. In this study, we investigated the role of another Runt-domain protein, RUNX3, in Ewing sarcoma. RUNX3 participates in mesenchymal-derived bone formation and is a context dependent tumor suppressor and oncogene. RUNX3 was detected in all Ewing sarcoma cells examined, whereas RUNX2 was detected in only 73% of specimens. Like RUNX2, RUNX3 binds to EWS/FLI via its Runt domain. EWS/FLI prevented RUNX3 from activating the transcription of a RUNX-responsive reporter, p6OSE2. Stable suppression of RUNX3 expression in the Ewing sarcoma cell line A673 delayed colony growth in anchorage independent soft agar assays and reversed expression of EWS/FLI-responsive genes. These results demonstrate an important role for RUNX3 in Ewing sarcoma. RNA-seq to compare transcriptiome of control A673 ewing sarcoma cells stably expression a non-target or RUNX3 shRNA
2014-05-01 | E-GEOD-56900 | biostudies-arrayexpress
Project description:EWS-FLI-1 was silenced by an shRNA in A673 Ewing sarcoma cells and the resulting alterations in the secretome was analyzed by GeLC-MS/MS approach (six gel slices for each sample, luciferase shRNA-expressing cell secretome as control)
2021-07-06 | PXD016052 | Pride
Project description:The transcriptional profile of LSD1 knockdown in A673 Ewing sarcoma cells mirrors that of EWS/FLI knockdown and LSD1 small molecule inhibition (SP-2509)
2019-05-03 | GSE98786 | GEO