HDAC inhibitors in synovial sarcoma cells
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ABSTRACT:
PROVIDER: EGAS00001002637 | EGA |
REPOSITORIES: EGA
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Project description:Cellular identity is determined by its gene expression programs. The ability of the cell to change its identity and produce cell types outside its lineage is achieved by the activity of transcription controllers capable of reprogramming differentiation gene networks. The synovial sarcoma associated protein, SYT-SSX2, reprograms myogenic progenitors and human bone marrow-derived mesenchymal stem cells (BMMSCs) by dictating their commitment to a pro-neural lineage. It fulfills this function by directly targeting an extensive array of neural-specific genes as well as genes of developmental pathway mediators. Concomitantly, the ability of both myoblasts and BMMSCs to differentiate into their normal myogenic and adipogenic lineages was compromised. Synovial sarcoma is believed to arise in mesenchymal stem cells where formation of the t(X;18) translocation product, SYT-SSX, constitutes the primary event in the cancer. SYT-SSX is therefore believed to initiate tumorigenesis in its target stem cell. The data presented here allow a glimpse at the initial events that likely occur when SYT-SSX2 is first expressed and its dominant function in subverting the nuclear program of the stem cell, leading to its aberrant differentiation, as a first step toward transformation. In addition, we identified the fibroblast growth factor receptor gene, Fgfr2, as one occupied and upregulated by SYT-SSX2. Knockdown of FGFR2 in both BMMSCs and synovial sarcoma cells abrogated their growth and attenuated their neural phenotype. These results support the notion that the SYT-SSX2 nuclear function and differentiation effects are conserved throughout sarcoma development and are required for its maintenance beyond the initial phase. They also provide the stem cell regulator, FGFR2 as a promising candidate target for future synovial sarcoma therapy. Refer to individual Series
2011-09-25 | E-GEOD-26565 | biostudies-arrayexpress
Project description:SS18-SSX fusion proteins play a central role in synovial sarcoma development, however, genetic network and mechanisms of synovial sarcomagenesis remain largely unknown. To clarify such unknown mechanisms, we have established a new ex vivo mouse model for synovial sarcoma, using retrovirus-mediated gene transfer of SS18-SSX1 to mouse embryonic mesenchymal cells followed by subcutaneous transplantation into nude mice. This approach successfully induced subcutaneous tumors in 100% of recipients, showing invasive proliferation of short spindle tumor cells with occasional biphasic appearance. Cytokeratin expression was observed in epithelial components in tumors and expression of TLE1 and BCL2 was also shown. Gene expression profiling indicates modulation of the SWI/SNF pathway by introduction of SS18-SSX1 into mesenchymal cells, and upregulation of Tle1 and Atf2 in tumors. Collectively, these findings indicate the model exhibits typical phenotypes of human synovial sarcoma. Retroviral tagging of the tumor identified 15 common retroviral integration sites with the Dnm3 locus as the most frequent in 30 mouse synovial sarcomas. Up-regulation of micro RNAs miR-199a2 and miR-214 within the Dnm3 locus was observed. Co-introduction of SS18-SSX1 and miR-214 indeed accelerated sarcoma onset, indicating that miR-214 is a cooperative onco-miR in synovial sarcomagenesis. miR-214 functions in the cell non-autonomous manner, promoting cytokine gene expression such as Cxcl15/IL8. We have succeeded to generate a novel mouse model for human synovial sarcoma. As miR-214 overexpression in human synovial sarcoma was reported, our results underscore the important role of miR-214 in tumor development and disease progression. We used microarrays to detail the global program of gene expression in mouse synovial sarcoma and embryonic mesenchymal cells
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Project description:To identify molecular biomarkers that are useful for diagnosis and its targeting treatment, we analysed expression profile of synovial sarcoma tissue. In the present study, we studied gene expression profiles comparing 11 cases of synovial sarcoma.
2015-07-23 | E-GEOD-65532 | biostudies-arrayexpress
Project description:MicroRNAs (miRNAs) are non-coding small RNAs that function as an endogenous regulator of gene expression. Their dysregulation has been implicated in the development of several cancers. However, the status of miRNA in soft tissue sarcomas has not yet been thoroughly investigated. This study examined the global miRNA expression in synovial sarcoma and compared the results to those in another translocation-associated sarcoma, the Ewing family of tumors, and in normal skeletal muscle. The 3D-Gene miRNA microarray platform (Toray, Kamakura, Japan) and unsupervised hierarchical clustering revealed a distinct expression pattern of miRNAs in synovial sarcoma from Ewing tumors and skeletal muscle. Thirty-five of the more than 700 miRNAs analyzed were differentially expressed in synovial sarcomas in comparison to other tissue types. There were 21 significantly up-regulated miRNAs, including some miRNAs, such as let-7e, miR-99b and miR-125a-3p, clustered within the same chromosomal loci. Quantitative reverse transcription-polymerase chain reaction also demonstrated that these miRNAs were over-expressed in synovial sarcomas. The down-regulation of let-7e and miR-99b by anti-miR miRNA inhibitors resulted in the suppression of the proliferation of synovial sarcoma cells, and modulated the expression of their putative targets, HMGA2 and SMARCA5, suggesting that these molecules have a potential oncogenic role. The unique miRNA expression pattern including the over-expressed miRNA clusters in synovial sarcoma warrants further investigation in order to develop a better understanding of the oncogenic mechanisms and future therapeutic strategies for synovial sarcoma. Ten synovial sarcomas, five Ewing tumors and five normal skeletal muscle specimens are analyzed.
2010-10-21 | E-GEOD-18546 | biostudies-arrayexpress
Project description:Poorly differentiated type synovial sarcoma (PDSS) is a variant of synovial sarcoma characterized by predominantly round or short-spindled cells. Although accumulating evidence from clinicopathological studies suggests a strong association between this variant of synovial sarcoma and poor prognosis, little has been reported on the molecular basis of PDSS. To gain insight into the mechanism(s) that underlie the emergence of PDSS, we analyzed the gene expression profiles of 34 synovial sarcoma clinical samples, including 5 cases of PDSS, using an oligonucleotide microarray. In an unsupervised analysis, the 34 samples fell into 3 groups that correlated highly with histological subtype, namely, monophasic, biphasic, and poorly differentiated types. PDSS was characterized by down-regulation of genes associated with neuronal and skeletal development and cell adhesion, and up-regulation of genes on a specific chromosomal locus, 8q21.11. This locus-specific transcriptional activation in PDSS was confirmed by reverse transcriptase (RT)-PCR analysis of 9 additional synovial sarcoma samples. Our results indicate that PDSS tumors constitute a distinct genetic group based on expression profiles. 34 SYT-SSX fusion transcript-positive SS samples, consisting of 21 MSS, 8 BSS and 5 PDSS cases, were analyzed using an oligonucleotide microarray using a GeneChip Human Genome U133 plus 2.0 array (Affymetrix).
2010-09-01 | E-GEOD-20196 | biostudies-arrayexpress
Project description:Poorly differentiated type synovial sarcoma (PDSS) is a variant of synovial sarcoma characterized by predominantly round or short-spindled cells. Although accumulating evidence from clinicopathological studies suggests a strong association between this variant of synovial sarcoma and poor prognosis, little has been reported on the molecular basis of PDSS. To gain insight into the mechanism(s) that underlie the emergence of PDSS, we analyzed the gene expression profiles of 34 synovial sarcoma clinical samples, including 5 cases of PDSS, using an oligonucleotide microarray. In an unsupervised analysis, the 34 samples fell into 3 groups that correlated highly with histological subtype, namely, monophasic, biphasic, and poorly differentiated types. PDSS was characterized by down-regulation of genes associated with neuronal and skeletal development and cell adhesion, and up-regulation of genes on a specific chromosomal locus, 8q21.11. This locus-specific transcriptional activation in PDSS was confirmed by reverse transcriptase (RT)-PCR analysis of 9 additional synovial sarcoma samples. Our results indicate that PDSS tumors constitute a distinct genetic group based on expression profiles.
2010-09-01 | GSE20196 | GEO
Project description:MicroRNAs (miRNAs) are non-coding small RNAs that function as an endogenous regulator of gene expression. Their dysregulation has been implicated in the development of several cancers. However, the status of miRNA in soft tissue sarcomas has not yet been thoroughly investigated. This study examined the global miRNA expression in synovial sarcoma and compared the results to those in another translocation-associated sarcoma, the Ewing family of tumors, and in normal skeletal muscle. The 3D-Gene miRNA microarray platform (Toray, Kamakura, Japan) and unsupervised hierarchical clustering revealed a distinct expression pattern of miRNAs in synovial sarcoma from Ewing tumors and skeletal muscle. Thirty-five of the more than 700 miRNAs analyzed were differentially expressed in synovial sarcomas in comparison to other tissue types. There were 21 significantly up-regulated miRNAs, including some miRNAs, such as let-7e, miR-99b and miR-125a-3p, clustered within the same chromosomal loci. Quantitative reverse transcription-polymerase chain reaction also demonstrated that these miRNAs were over-expressed in synovial sarcomas. The down-regulation of let-7e and miR-99b by anti-miR miRNA inhibitors resulted in the suppression of the proliferation of synovial sarcoma cells, and modulated the expression of their putative targets, HMGA2 and SMARCA5, suggesting that these molecules have a potential oncogenic role. The unique miRNA expression pattern including the over-expressed miRNA clusters in synovial sarcoma warrants further investigation in order to develop a better understanding of the oncogenic mechanisms and future therapeutic strategies for synovial sarcoma.
2010-10-21 | GSE18546 | GEO
Project description:Cellular identity is determined by its gene expression programs. The ability of the cell to change its identity and produce cell types outside its lineage is achieved by the activity of transcription controllers capable of reprogramming differentiation gene networks. The synovial sarcoma associated protein, SYT-SSX2, reprograms myogenic progenitors and human bone marrow-derived mesenchymal stem cells (BMMSCs) by dictating their commitment to a pro-neural lineage. It fulfills this function by directly targeting an extensive array of neural-specific genes as well as genes of developmental pathway mediators. Concomitantly, the ability of both myoblasts and BMMSCs to differentiate into their normal myogenic and adipogenic lineages was compromised. Synovial sarcoma is believed to arise in mesenchymal stem cells where formation of the t(X;18) translocation product, SYT-SSX, constitutes the primary event in the cancer. SYT-SSX is therefore believed to initiate tumorigenesis in its target stem cell. The data presented here allow a glimpse at the initial events that likely occur when SYT-SSX2 is first expressed and its dominant function in subverting the nuclear program of the stem cell, leading to its aberrant differentiation, as a first step toward transformation. In addition, we identified the fibroblast growth factor receptor gene, Fgfr2, as one occupied and upregulated by SYT-SSX2. Knockdown of FGFR2 in both BMMSCs and synovial sarcoma cells abrogated their growth and attenuated their neural phenotype. These results support the notion that the SYT-SSX2 nuclear function and differentiation effects are conserved throughout sarcoma development and are required for its maintenance beyond the initial phase. They also provide the stem cell regulator, FGFR2 as a promising candidate target for future synovial sarcoma therapy. This SuperSeries is composed of the SubSeries listed below.
2011-09-26 | GSE26565 | GEO