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BMC Cancer

, 17:107

Cell and molecular biology


BackgroundDesmoplastic small round cell tumor DSRCT is a rare and highly aggressive disease, that can be described as a member of the family of small round blue cell tumors. The molecular diagnostic marker is the t11;22p13;q12 translocation, which creates an aberrant transcription factor, EWS-WT1, that underlies the oncogenesis of DSRCT. Current treatments are not very effective so new active drugs are needed. Trabectedin, now used as a single agent for the treatment of soft tissue sarcoma, was reported to be active in some pre-treated DSRCT patients. Using JN-DSRCT-1, a cell line derived from DSRCT expressing the EWS-WT1 fusion protein, we investigated the ability of trabectedin to modify the function of the chimeric protein, as in other sarcomas expressing fusion proteins. After detailed characterization of the EWS-WT1 transcripts structure, we investigated the mode of action of trabectedin, looking at the expression and function of the oncogenic chimera.

MethodsWe characterized JN-DSRCT-1 cells using cellular approaches FISH, Clonogenicity assay and molecular approaches Sanger sequencing, ChIP, GEP.

ResultsJN-DSRCT-1 cells were sensitive to trabectedin at nanomolar concentrations. The cell line expresses different variants of EWS-WT1, some already identified in patients. EWS-WT1 mRNA expression was affected by trabectedin and chimeric protein binding on its target gene promoters was reduced. Expression profiling indicated that trabectedin affects the expression of genes involved in cell proliferation and apoptosis.

ConclusionsThe JN-DSRCT-1 cell line, in vitro, is sensitive to trabectedin: after drug exposure, EWS-WT1 chimera expression decreases as well as binding on its target promoters. Probably the heterogeneity of chimera transcripts is an obstacle to precisely defining the molecular mode of action of drugs, calling for further cellular models of DSRCT, possibly growing in vivo too, to mimic the biological complexity of this disease.

KeywordsDSRCT JN-DSRCT-1 Trabectedin AbbreviationsChIPChromatin immuno precipitation

DEGsDifferentially expressed genes

DSRCTDesmoplastic small round cell tumor

FISHFluorescence in situ hybridization

GEPGene expression profiling

Electronic supplementary materialThe online version of this article doi:10.1186-s12885-017-3091-1 contains supplementary material, which is available to authorized users.

Autor: S. Uboldi - I. Craparotta - G. Colella - E. Ronchetti - L. Beltrame - S. Vicario - S. Marchini - N. Panini - G. Dagrada -


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