EWS/ETS Regulates the Expression of the Dickkopf Family in Ewing Family Tumor Cells

BACKGROUND: The Dickkopf (DKK) family comprises a set of proteins that function as regulators of Wnt/beta-catenin signaling and has a crucial role in development. Recent studies have revealed the involvement of this family in tumorigenesis, however their role in tumorigenesis is still remained unclear. METHODOLOGY/PRINCIPAL FINDINGS: We found increased expression of DKK2 but decreased expression of DKK1 in Ewing family tumor (EFT) cells. We showed that EFT-specific EWS/ETS fusion proteins enhance the DKK2 promoter activity, but not DKK1 promoter activity, via ets binding sites (EBSs) in the 5' upstream region. EWS/ETS-mediated transactivation of the promoter was suppressed by the deletion and mutation of EBSs located upstream of the DKK2 gene. Interestingly, the inducible expression of EWS/ETS resulted in the strong induction of DKK2 expression and inhibition of DKK1 expression in human primary mesenchymal progenitor cells that are thought to be a candidate of cell origin of EFT. In addition, using an EFT cell line SK-ES1 cells, we also demonstrated that the expression of DKK1 and DKK2 is mutually exclusive, and the ectopic expression of DKK1, but not DKK2, resulted in the suppression of tumor growth in immuno-deficient mice. CONCLUSIONS/SIGNIFICANCE: Our results suggested that DKK2 could not functionally substitute for DKK1 tumor-suppressive effect in EFT. Given the mutually exclusive expression of DKK1 and DKK2, EWS/ETS regulates the transcription of the DKK family, and the EWS/ETS-mediated DKK2 up-regulation could affect the tumorigenicity of EFT in an indirect manner

Grouping facilitates avoidance of parasites by fish

Background. Parasite distribution is often highly heterogeneous, and intensity of infection depends, among other things, on how well hosts can avoid areas with a high concentration of parasites. We studied the role of fish behaviour in avoiding microhabitats with a high infection risk using Oncorhynchus mykiss and cercariae of Diplostomum pseudospathaceum as a model. Spatial distribution of parasites in experimental tanks was highly heterogeneous. We hypothesized that fish in groups are better at recognizing a parasitized area and avoiding it than solitary fish. Methods. Number of fish, either solitary or in groups of 5, was recorded in different compartments of a shuttle tank where fish could make a choice between areas with different risk of being infected. Intensity of infection was assessed and compared with the number of fish recorded in the compartment with parasites and level of fish motility. Results. Both solitary fish and fish in groups avoided parasitized areas, but fish in groups avoided it more strongly and thus acquired significantly fewer parasites than solitary fish. Prevalence of infection among grouped and solitary fish was 66 and 92 %, respectively, with the mean abundance two times higher in the solitary fish. Between-individual variation in the number of parasites per fish was higher in the “groups” treatment (across all individuals) than in the “solitary” treatment. Avoidance behaviour was more efficient when fish were allowed to explore the experimental arena prior to parasite exposure. High motility of fish was shown to increase the acquisition of D. pseudospathaceum. Conclusion. Fish in groups better avoided parasitized habitat, and acquired significantly fewer parasites than solitary fish. We suggest that fish in groups benefit from information about parasites gained from other members of a group. Grouping behaviour may be an efficient mechanism of parasite avoidance, together with individual behaviour and immune responses of fishes. Avoidance of habitats with a high parasite risk can be an important factor contributing to the evolution and maintenance of grouping behaviour in fish.peerReviewe