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Gene expression analysis of human pediatric mesenchymal stem cells (hpMSCs) upon expression of EWS-FLI-1

ABSTRACT: Cancer stem cells (CSCs) display plasticity and self-renewal properties reminiscent of normal tissue stem cells, but the events responsible for their emergence remain obscure. We recently identified CSCs in Ewing sarcoma family tumors (ESFTs) and showed that they retain mesenchymal stem cell (MSC) plasticity. In the present study, we addressed the mechanisms that underlie ESFT CSC development. We show that the EWS-FLI-1 fusion gene, associated with 85%-90% of ESFTs and believed to initiate their pathogenesis, induces expression of the embryonic stem cell (ESC) genes OCT4, SOX2, and NANOG in human pediatric MSCs (hpMSCs) but not in their adult counterparts. Moreover, under appropriate culture conditions, hpMSCs expressing EWS-FLI-1 generate a cell subpopulation displaying ESFT CSC features in vitro. We further demonstrate that induction of the ESFT CSC phenotype is the result of the combined effect of EWS-FLI-1 on its target gene expression and repression of microRNA-145 (miRNA145) promoter activity. Finally, we provide evidence that EWS-FLI-1 and miRNA-145 function in a mutually repressive feedback loop and identify their common target gene, SOX2, in addition to miRNA145 itself, as key players in ESFT cell differentiation and tumorigenicity. Our observations provide insight for the first time into the mechanisms whereby a single oncogene can reprogram primary cells to display a CSC phenotype. 4 samples of hpMSCs expressing EWS-FLI-1 vs. 4 matched samples of empty-vector-infected cells.

ORGANISM(S): Homo sapiens

SUBMITTER: Paolo Provero

PROVIDER: E-GEOD-31215 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Gene expression analysis of human pediatric mesenchymal stem cells (hpMSCs) upon expression of EWS-FLI-1

Project description:Cancer stem cells (CSCs) display plasticity and self-renewal properties reminiscent of normal tissue stem cells, but the events responsible for their emergence remain obscure. We recently identified CSCs in Ewing sarcoma family tumors (ESFTs) and showed that they retain mesenchymal stem cell (MSC) plasticity. In the present study, we addressed the mechanisms that underlie ESFT CSC development. We show that the EWS-FLI-1 fusion gene, associated with 85%-90% of ESFTs and believed to initiate their pathogenesis, induces expression of the embryonic stem cell (ESC) genes OCT4, SOX2, and NANOG in human pediatric MSCs (hpMSCs) but not in their adult counterparts. Moreover, under appropriate culture conditions, hpMSCs expressing EWS-FLI-1 generate a cell subpopulation displaying ESFT CSC features in vitro. We further demonstrate that induction of the ESFT CSC phenotype is the result of the combined effect of EWS-FLI-1 on its target gene expression and repression of microRNA-145 (miRNA145) promoter activity. Finally, we provide evidence that EWS-FLI-1 and miRNA-145 function in a mutually repressive feedback loop and identify their common target gene, SOX2, in addition to miRNA145 itself, as key players in ESFT cell differentiation and tumorigenicity. Our observations provide insight for the first time into the mechanisms whereby a single oncogene can reprogram primary cells to display a CSC phenotype.

2011-08-05 | GSE31215 | GEO

MicroRNA expression profiling of Ewing sarcoma cancer stem cells

Project description:We have recently demonstrated that human paediatric mesenchymal stem cells can be reprogrammed toward a Ewing’s sarcoma family tumor (ESFT) cancer stem cell (CSC) phenotype by mechanisms that implicate microRNAs (miRNAs). Here, we show that the miRNA profile of ESFT CSC is shared by embryonic stem cells and CSC from divergent tumor types. We also provide evidence that the miRNA profile of ESFT CSC is the result of reversible disruption of TARBP2-dependent miRNA maturation. Restoration of TARBP2 activity and systemic delivery of synthetic forms of either of two of its targets, miRNA-143 or miRNA-145, inhibited ESFT CSC clonogenicity and tumor growth in vivo. Our observations suggest that CSC self-renewal and tumor initiation may depend on deregulation of TARBP2-dependent miRNA expression. 2 samples of primary Ewing sarcomas, divided into CD133+ and CD133- fractions. One sample of EWS-FLI1 expressing human pediatric mesenchymal stem cells, divided into CD133+ and CD133- fractions. One sample of STA-ET-8.2 cells, divided into CD133+ and CD133- fractions.

2012-06-19 | E-GEOD-30513 | biostudies-arrayexpress

MicroRNA expression profiling of Ewing sarcoma cell lines

Project description:Ewing’s sarcoma family tumors (ESFT) are the second most common bone malignancy in children and young adults, characterized by the expression of a unique chromosomal translocation, that in 85% of cases lead to the expression of the EWS-FLI-1 fusion protein. ESW-FLI-1 functions as an aberrant transcription factor that can both induce and suppress its target genes. We have recently demonstrated that microRNA (miRNA) 145 is a direct EWS-FLI-1 target implicated in ESFT development. Here, we use global miRNA array profiling to show that ESFT display a distinct miRNA signature characterized by the induction or repression of a limited number of miRNAs, including the oncogenic and tumor suppressor miRNA 17-92 and let-7 families, respectively. We demonstrate that repression of the let-7 family member let-7a may be due to direct binding of EWS-FLI-1 to the let-7a promoter and that it participates in the tumorigenic potential of ESFT cells in vivo. The mechanism whereby let-7a repression enhances ESFT growth is shown to be the induction of its target gene HMGA2, as overexpression of let-7a or repression of HMGA2 blocked ESFT cell tumorigenicity. Consistent with these observations, systemic delivery of synthetic let-7a that restored its expression in tumor cells and decreased HMGA2 expression inhibited ESFT growth in vivo. Our observations provide evidence that deregulation of let-7a target gene expression participates in ESFT development and identify let-7a as a promising new therapeutic target for one of the most aggressive pediatric malignancies.

2011-12-27 | GSE29085 | GEO

MicroRNA expression profiling of Ewing sarcoma spheres vs. adherent cells

2012-06-20 | GSE31145 | GEO

MicroRNA expression profiling of Ewing sarcoma cell lines upon TARBP2 depletion

2012-06-20 | GSE31144 | GEO

MicroRNA expression profiling of Ewing sarcoma cancer stem cells

2012-06-20 | GSE30513 | GEO

MicroRNA expression profiling of Ewing sarcoma cell lines upon TARBP2 depletion

Project description:We have recently demonstrated that human paediatric mesenchymal stem cells can be reprogrammed toward a Ewing’s sarcoma family tumor (ESFT) cancer stem cell (CSC) phenotype by mechanisms that implicate microRNAs (miRNAs). Here, we show that the miRNA profile of ESFT CSC is shared by embryonic stem cells and CSC from divergent tumor types. We also provide evidence that the miRNA profile of ESFT CSC is the result of reversible disruption of TARBP2-dependent miRNA maturation. Restoration of TARBP2 activity and systemic delivery of synthetic forms of either of two of its targets, miRNA-143 or miRNA-145, inhibited ESFT CSC clonogenicity and tumor growth in vivo. Our observations suggest that CSC self-renewal and tumor initiation may depend on deregulation of TARBP2-dependent miRNA expression. 3 Ewing sarcoma cell lines: comparison between TARBP2 silencing by shRNA and control.

2012-06-19 | E-GEOD-31144 | biostudies-arrayexpress

MicroRNA expression profiling of Ewing sarcoma spheres vs. adherent cells

Project description:We have recently demonstrated that human paediatric mesenchymal stem cells can be reprogrammed toward a Ewing’s sarcoma family tumor (ESFT) cancer stem cell (CSC) phenotype by mechanisms that implicate microRNAs (miRNAs). Here, we show that the miRNA profile of ESFT CSC is shared by embryonic stem cells and CSC from divergent tumor types. We also provide evidence that the miRNA profile of ESFT CSC is the result of reversible disruption of TARBP2-dependent miRNA maturation. Restoration of TARBP2 activity and systemic delivery of synthetic forms of either of two of its targets, miRNA-143 or miRNA-145, inhibited ESFT CSC clonogenicity and tumor growth in vivo. Our observations suggest that CSC self-renewal and tumor initiation may depend on deregulation of TARBP2-dependent miRNA expression. 2 Ewing sarcoma primary samples: comparison between spheres and derived adherent cells.

2012-06-19 | E-GEOD-31145 | biostudies-arrayexpress

RNA immunoprecipitation (RIP)-Chip analysis for EWS-bound mRNA

Project description:Although EWS/FLI-1 fusion protein is responsible for most Ewing’s sarcoma family tumors (ESFT), the function of native EWS remains largely unknown. Here, we first showed that EWS repressed protein expression in a tethering assay. mRNAs bound to EWS were determined by RNA-immunoprecipitation Chip assay, and one of them, proline-rich Akt substrate of 40 kDa (PRAS40) mRNA, directly interacted with EWS. The inhibitor of AKT, API-2, repressed ESFT cell proliferation. We demonstrate that EWS negatively regulated PRAS40 protein expression through binding to PRAS40 3’UTR. Furthermore, PRAS40 knockdown inhibited the proliferation and metastatic potential of ESFT cells.

2012-01-16 | GSE29313 | GEO

RNA immunoprecipitation (RIP)-Chip analysis for EWS-bound mRNA

Project description:Although EWS/FLI-1 fusion protein is responsible for most EwingM-bM-^@M-^Ys sarcoma family tumors (ESFT), the function of native EWS remains largely unknown. Here, we first showed that EWS repressed protein expression in a tethering assay. mRNAs bound to EWS were determined by RNA-immunoprecipitation Chip assay, and one of them, proline-rich Akt substrate of 40 kDa (PRAS40) mRNA, directly interacted with EWS. The inhibitor of AKT, API-2, repressed ESFT cell proliferation. We demonstrate that EWS negatively regulated PRAS40 protein expression through binding to PRAS40 3M-bM-^@M-^YUTR. Furthermore, PRAS40 knockdown inhibited the proliferation and metastatic potential of ESFT cells. Cytoplasmic lysates or whole cell lysates were prepared from HeLa S3 cells transfected with pFLAG-EWS , and incubated with anti-FLAG M2 Affinity Gel (Sigma) at 4M-BM-0C for 2 h. RNAs from lysates and immunoprecipitates were analysed using GeneChip Human Genome U133 Plus 2.0 Array (Affymetrix).

2012-01-16 | E-GEOD-29313 | biostudies-arrayexpress

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