EWS-Fli1 antisense oligodeoxynucleotide inhibits proliferation of human Ewing's sarcoma and primitive neuroectodermal tumor cells.

Tanaka, Kazuhiro; Iwakuma, Tomoo; Harimaya, Katsumi; Sato, Hideshi; Iwamoto, Yukihide

doi:10.1172/jci119152

Cited by 253 publications

(201 citation statements)

References 41 publications

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“…Variations in the efficiency of clones to display a transformed phenotype appeared to correlate with the level of the EWS/FLI-1 fusion proteins rather than the species from which the sequences were derived. These findings validate at a protein level previous reports that suggested a correlation between the mRNA levels of human EWS/FLI-1 and the proliferation rate of ES/PNET cells (Tanaka et al, 1997). These data indicate the feasibility and validity of a murine model for ES/PNET, which would provide a valuable resource for elucidating the mechanisms of EWS/FLI-1 transformation and the development of a model in which to test novel therapeutic strategies.…”

Section: Discussionsupporting

confidence: 88%

“…Indeed, the EWS/FLI-1 fusion protein may also have alternate activities since mutation of the Ets DBD does not ablate all transforming abilities and EWS/FLI-1 can also affect mRNA splicing (Jaishankar et al, 1999;Knoop and Baker, 2001;Welford et al, 2001). While the use of antisense oligonucleotides or transcripts to inhibit EWS/FLI-1 expression or suppression of a variety of signalling pathways reduced the tumorigenic potential of ES/PNET cells (Ouchida et al, 1995;Kovar et al, 1996;Tanaka et al, 1997;Toretsky et al, 1997), these reports confirm the central role of EWS/FLI-1 in ES/PNET, but do not address the mechanism by which EWS/FLI-1 acts. Since cancer rarely results from a single mutation and, like other cancers, ES/PNET cells contain other mutations (e.g.…”

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confidence: 99%

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Transformation induced by Ewing's sarcoma associated EWS/FLI-1 is suppressed by KRAB/FLI-1

Chan

Wilson

et al. 2003

Br J Cancer

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Ewing's sarcoma is a childhood bone tumour with poor prognosis, most commonly associated with a t(11;22)(q24;q12) reciprocal translocation that fuses the EWS and FLI-1 genes, resulting in the production of an aberrant chimeric transcription factor EWS/FLI-1. To elucidate the mechanisms by which EWS/FLI-1 mediates transformation in mouse models, we have generated a murine Ews/Fli-1 fusion protein. We demonstrate that this protein transforms fibroblast cells in vitro similar to human EWS/FLI-1 as demonstrated by serum and anchorage-independent growth, the formation of tumours in nude mice and elevation of the oncogenic marker c-myc. Furthermore, transformation of these cells was inhibited by a specific repressor, KRAB/FLI-1. The KRAB/FLI-1 repressor also suppressed the tumorigenic phenotype of a human Ewing's sarcoma cell line. These findings suggest that the transformed phenotype of Ewing's sarcoma cells can be reversed by using the sequence-specific FLI-1-DNA-binding domain to target a gene repressor domain. The inhibition of EWS/FLI-1 is the first demonstration of the KRAB domain suppressing the action of an ETS factor. This approach provides potential avenues for the elucidation of the biological mechanisms of EWS/FLI-1 oncogenesis and the development of novel therapeutic strategies.

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Section: Discussionsupporting

confidence: 88%

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confidence: 99%

Transformation induced by Ewing's sarcoma associated EWS/FLI-1 is suppressed by KRAB/FLI-1

Chan

Wilson

et al. 2003

Br J Cancer

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“…Cell growth assay was carried out as described (Tanaka et al, 1997). Briefly, various cell lines were seeded on 35-mm culture dishes at 10 5 viable cells/dish with 1.5 ml of medium, and incubated at 37˚C.…”

Section: Cell Growth Assaymentioning

confidence: 99%

“…Composition of the primers used for PCR has been described previously (Wang et al, 1996;Tanaka et al, 1997). PCR reactions were performed in a final volume of 50 µl for 30 cycles.…”

Section: Rt-pcrmentioning

confidence: 99%

Downregulation and forced expression of EWS-Fli1 fusion gene results in changes in the expression of G1regulatory genes

et al. 2001

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Chromosomal translocation t(11;22)(q24:q12) is detected in approximately 90% of tumours of the Ewing family (ET). This translocation results in EWS-Fli1 gene fusion which produces a EWS-Fli1 fusion protein acting as an aberrant transcriptional activator. We previously reported that the inhibition of EWS-Fli1 expression caused the G 0 /G 1 arrest of ET cells. We, therefore, hypothesized that EWS-Fli1 may affect the expression of G 1 regulatory genes. Downregulation of EWS-Fli1 fusion proteins was observed 48 hours after the treatment with EWS-Fli1 antisense oligonucleotides. The expressions of G 1 cyclins, cyclin D1 and cyclin E, were markedly decreased in parallel with the reduction of EWS-Fli1 fusion protein. On the other hand, the expression of p21 and p27, which are important cyclin-dependent kinase inhibitors (CKIs) for G 1 –S transition, was dramatically increased after the treatment with EWS-Fli1 antisense oligonucleotides. RT-PCR analysis showed that alteration of the expressions of the cyclins and CKIs occurred at the mRNA level. Furthermore, transfection of EWS-Fli1 cDNA to NIH3T3 caused transformation of the cells and induction of the expression of cyclin D1 and E. Clinical samples of ET also showed a high level of expression of cyclin D1 mRNA, whereas mRNAs for p21 and p27 were not detected in the samples. These findings strongly suggest that the G 1 –S regulatory genes may be involved in downstream of EWS-Fli1 transcription factor, and that the unbalanced expression of G 1 –S regulatory factors caused by EWS-Fli1 may lead to the tumorigenesis of ET. © 2001 Cancer Research Campaign http://www. bjcancer.com

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“…The EWS/FLI-1 protein is mainly localized in the cell nucleus, and there is evidence that it functions as a transcription activator (Bailly et al, 1994). The fusion protein has been found to be important for cell growth and tumor transformation (Tanaka et al, 1997;Toretsky et al, 1997). Recently, Hahm et al (1999) provided evidence that transformation growth factor-b type II receptor gene is a target for EWS/FLI-1.…”

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confidence: 99%

A link between basic fibroblast growth factor (bFGF) and EWS/FLI-1 in Ewing's sarcoma cells

et al. 2000

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EWS-Fli1 antisense oligodeoxynucleotide inhibits proliferation of human Ewing's sarcoma and primitive neuroectodermal tumor cells.

Cited by 253 publications

References 41 publications

Transformation induced by Ewing's sarcoma associated EWS/FLI-1 is suppressed by KRAB/FLI-1

Transformation induced by Ewing's sarcoma associated EWS/FLI-1 is suppressed by KRAB/FLI-1

Downregulation and forced expression of EWS-Fli1 fusion gene results in changes in the expression of G1regulatory genes

A link between basic fibroblast growth factor (bFGF) and EWS/FLI-1 in Ewing's sarcoma cells

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