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. 2009;4(4):e5415.
doi: 10.1371/journal.pone.0005415. Epub 2009 Apr 30.

A molecular function map of Ewing's sarcoma

Maximilian Kauer  1 , Jozef Ban, Reinhard Kofler, Bob Walker, Sean Davis, Paul Meltzer, Heinrich Kovar
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VSports - A molecular function map of Ewing's sarcoma

Maximilian Kauer et al. PLoS One. 2009.

Abstract

Background: EWS-FLI1 is a chimeric ETS transcription factor that is, due to a chromosomal rearrangement, specifically expressed in Ewing's sarcoma family tumors (ESFT) and is thought to initiate the development of the disease. Previous genomic profiling experiments have identified EWS-FLI1-regulated genes and genes that discriminate ESFT from other sarcomas, but so far a comprehensive analysis of EWS-FLI1-dependent molecular functions characterizing this aggressive cancer is lacking. VSports手机版.

Methodology/principal findings: In this study, a molecular function map of ESFT was constructed based on an integrative analysis of gene expression profiling experiments following EWS-FLI1 knockdown in a panel of five ESFT cell lines, and on gene expression data from the same platform of 59 primary ESFT. Out of 80 normal tissues tested, mesenchymal progenitor cells (MPC) were found to fit the hypothesis that EWS-FLI1 is the driving transcriptional force in ESFT best and were therefore used as the reference tissue for the construction of the molecular function map V体育安卓版. The interrelations of molecular pathways were visualized by measuring the similarity among annotated gene functions by gene sharing. The molecular function map highlighted distinct clusters of activities for EWS-FLI1 regulated genes in ESFT and revealed a striking difference between EWS-FLI1 up- and down-regulated genes: EWS-FLI1 induced genes mainly belong to cell cycle regulation, proliferation, and response to DNA damage, while repressed genes were associated with differentiation and cell communication. .

Conclusions/significance: This study revealed that EWS-FLI1 combines by distinct molecular mechanisms two important functions of cellular transformation in one protein, growth promotion and differentiation blockage V体育ios版. By taking MPC as a reference tissue, a significant EWS-FLI1 signature was discovered in ESFT that only partially overlapped with previously published EWS-FLI1-dependent gene expression patterns, identifying a series of novel targets for the chimeric protein in ESFT. Our results may guide target selection for future ESFT specific therapies. .

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Plot of Pearson correlation coefficients of corr(ΔET, ΔKD).
For each reference tissue tested (y-axis) the correlation coefficient between ΔET[ref] and ΔKD is shown (x-axis). While the distribution of correlation coefficients is generally skewed towards negative values the highest negative correlation is found for corr(ΔET[MPC], ΔKD).
Figure 2
Figure 2. ΔKD-ΔET plot.
Plot of relative gene expression values of the EWS-FLI1 knockdown compared to control (ΔKD, x-axis) and ESFT compared to reference (ΔET, y-axis). (A) reference = the mean of all tissues in the Novartis gene expression atlas, (B) reference = human mesenchymal progenitor cells (MPC). Genes for this plot were selected by applying an adjusted p-value cut-off: P<0.1 for ΔKD and ΔET. The Pearson correlation coefficients (R) between ΔKD and ΔET are indicated in the boxes.
Figure 3
Figure 3. Molecular Function Map of ESFT.
Functional groups (FG) from the DAVID analysis were aggregated by multidimensional scaling (MDS – A: EWS-FLI1 upregulated genes and C: EWS-FLI1 downregulated genes) and hierarchical clustering (B: EWS-FLI1 upregulated genes and D: EWS-FLI1 downregulated genes). In the MDS plots the x- and y-axis represent the first two dimensions of the MDS procedure (see Materials and Methods for details). Circles indicate the relative size (number of genes) of the annotation clusters. FGs with more than 60 genes are shown as solid circles, smaller FGs as dashed circles. The number of genes within each FG is indicated after the hyphen. The intersections of the circles are determined by their position in the plot and their size only and do not quantify the number of shared genes. However, FGs (circles) which share the same center indicate that the smaller gene set is a subset of the larger gene set. The heatmaps (B, D) show a hierarchical clustering (average linkage algorithm) of the FGs using the number of shared genes as distance measure (gDist – see Methods). Red indicates highest similarity (the smaller gene set is a subset of the larger one) and white the lowest similarity (no shared gene). Intermediate values for gDist are indicated as shades of orange/yellow.
Figure 4
Figure 4. Significant MSigDB gene sets.
Significant MSigDB gene sets (c2, c3) from the pGSEA analysis were aggregated by hierarchical clustering. A: Gene sets significantly overlapping EWS-FLI1 upregulated genes, B: Gene sets significantly overlapping EWS-FLI1 downregulated genes.
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References

    1. Bernstein M, Kovar H, Paulussen M, Randall RL, Schuck A, et al. Ewing's Sarcoma Family of Tumors: Current Management. Oncologist. 2006;11:503–519. - PubMed (VSports app下载)
    1. Delattre O, Zucman J, Plougastel B, Desmaze C, Melot T, et al. Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature. 1992;359:162–165. - PubMed
    1. Kovar H. Context matters: The hen or egg problem in Ewing's sarcoma. Semin Cancer Biol. 2005;15:189–196. - V体育官网 - PubMed
    1. Hancock JD, Lessnick SL. A transcriptional profiling meta-analysis reveals a core EWS-FLI gene expression signature. Cell Cycle. 2008;7:250–256. - PubMed
    1. Baird K, Davis S, Antonescu CR, Harper UL, Walker RL, et al. Gene expression profiling of human sarcomas: insights into sarcoma biology. Cancer Res. 2005;65:9226–9235. - "V体育平台登录" PubMed

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