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The oncogenic properties of EWS/WT1 of desmoplastic small round cell tumors are unmasked by loss of p53 in murine embryonic fibroblasts

Bandopadhayay, Pratiti, Jabbour, Anissa M, Riffkin, Christopher, Salmanidis, Marika, Gordon, Lavinia, Popovski, Dean, Rigby, Lin, Ashley, David M., Watkins, David N., Thomas, David M., Algar, Elizabeth and Ekert, Paul G. 2013, The oncogenic properties of EWS/WT1 of desmoplastic small round cell tumors are unmasked by loss of p53 in murine embryonic fibroblasts, BMC cancer, vol. 13, pp. 1-14, doi: 10.1186/1471-2407-13-585.

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Title The oncogenic properties of EWS/WT1 of desmoplastic small round cell tumors are unmasked by loss of p53 in murine embryonic fibroblasts
Author(s) Bandopadhayay, Pratiti
Jabbour, Anissa M
Riffkin, Christopher
Salmanidis, Marika
Gordon, Lavinia
Popovski, Dean
Rigby, Lin
Ashley, David M.
Watkins, David N.
Thomas, David M.
Algar, Elizabeth
Ekert, Paul G.
Journal name BMC cancer
Volume number 13
Article ID 585
Start page 1
End page 14
Total pages 14
Publisher BioMed Central
Place of publication London, Eng.
Publication date 2013-12-09
ISSN 1471-2407
Keyword(s) Animals
Apoptosis
Cell Cycle Checkpoints
Cell Proliferation
Cell Survival
Cells, Cultured
DNA Copy Number Variations
Daunorubicin
Desmoplastic Small Round Cell Tumor
Drug Resistance, Neoplasm
Fibroblasts
Humans
Mice
Mice, Transgenic
Nuclear Proteins
Oncogene Proteins, Fusion
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-mdm2
Radiation Tolerance
Transcriptome
Tumor Suppressor Protein p53
Wnt Signaling Pathway
Science & Technology
Life Sciences & Biomedicine
Oncology
Summary BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is characterized by the presence of a fusion protein EWS/WT1, arising from the t (11;22) (p13;q12) translocation. Here we examine the oncogenic properties of two splice variants of EWS/WT1, EWS/WT1-KTS and EWS/WT1 + KTS.
METHODS: We over-expressed both EWS/WT1 variants in murine embryonic fibroblasts (MEFs) of wild-type, p53+/- and p53-/- backgrounds and measured effects on cell-proliferation, anchorage-independent growth, clonogenicity after serum withdrawal, and sensitivity to cytotoxic drugs and gamma irradiation in comparison to control cells. We examined gene expression profiles in cells expressing EWS/WT1. Finally we validated our key findings in a small series of DSRCT.
RESULTS: Neither isoform of EWS/WT1 was sufficient to transform wild-type MEFs however the oncogenic potential of both was unmasked by p53 loss. Expression of EWS/WT1 in MEFs lacking at least one allele of p53 enhanced cell-proliferation, clonogenic survival and anchorage-independent growth. EWS/WT1 expression in wild-type MEFs conferred resistance to cell-cycle arrest after irradiation and daunorubicin induced apoptosis. We show DSRCT commonly have nuclear localization of p53, and copy-number amplification of MDM2/MDMX. Expression of either isoform of EWS/WT1 induced characteristic mRNA expression profiles. Gene-set enrichment analysis demonstrated enrichment of WNT pathway signatures in MEFs expressing EWS/WT1 + KTS. Wnt-activation was validated in cell lines with over-expression of EWS/WT1 and in DSRCT.
CONCLUSION: In conclusion, we show both isoforms of EWS/WT1 have oncogenic potential in MEFs with loss of p53. In addition we provide the first link between EWS/WT1 and Wnt-pathway signaling. These data provide novel insights into the function of the EWS/WT1 fusion protein which characterize DSRCT.
Language eng
DOI 10.1186/1471-2407-13-585
Field of Research 110106 Medical Biochemistry: Proteins and Peptides (incl Medical Proteomics)
111601 Cell Physiology
1112 Oncology And Carcinogenesis
Socio Economic Objective 920102 Cancer and Related Disorders
HERDC Research category C1.1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2013, Bandopadhayay et al.
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30068959

Document type: Journal Article
Collections: School of Medicine
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.