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2005 Fiscal Year Final Research Report Summary

Analysis on oncogenic mechanisms and therapeutic targets in Ewing's sarcoma

Research Project

Project/Area Number 14207057
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Orthopaedic surgery
Research InstitutionKYUSHU UNIVERSITY

Principal Investigator

IWAMOTO Yukihide  KYUSHU UNIVERSITY, Graduate School of Medical Sciences, Professor, 大学院・医学研究院, 教授 (00213322)

Co-Investigator(Kenkyū-buntansha) ODA Yoshinao  KYUSHU UNIVERSITY, Graduate School of Medical Sciences, Assistant Professor, 大学院・医学研究院, 講師 (70291515)
TANAKA Kazuhiro  Kyushu University, Hospital, Research Associate, 大学病院, 助手 (10274458)
Project Period (FY) 2002 – 2005
KeywordsEwing's Sarcoma / EWS-Fli1 / Fusion Gene / Molecular Target / Cell Cycle / p27 / p21 / Cyclin E
Research Abstract

The translocation t(11;22)(q24:q12) is a specific chromosomal abnormality detected in Ewing's sarcoma (ES). The translocation results in an EWS-Fli1 fusion gene, made up of the 5' half of the EWS gene on chromosome 22 fused to the 3' half of the Fli1 gene on chromosome 11. Recent studies have evaluated transforming potentials of the fusion gene products acting as an aberrant transcription factor. However, the biological significance of EWS-Fli1 is still unknown. We have reported that G1 cyclins including cyclin D1 and cyclin E were upregulated by EWS-Fli1, whereas CDK inhibitors, p21 and p27, were downregulated. These molecules are located in the upstream of retinoblastoma tumor suppressor gene Rb, therefore EWS-Fli1 might affect Rb pathway in ES leading to oncogenesis of the tumor. On the other hand, the abnormality in p53 pathway has not been well analyzed in ES yet. In the present study, we investigated the effects of EWS-Fli1 on p53 pathway and its function, especially the inductio … More n of apoptosis in ES cells. The immunoprecipitation assay revealed that EWS-Fli1 bound to p53 protein, and inhibited its function in p53 wild type ES cells. However, EWS-Fli1 did not significantly affect the expression of apoptosis-related genes located in the downstream of p53 transcription factor. The expression of p21, one of the target genes of p53, was inhibited by EWS-Fli1 via the suppression of the activity of p21 gene promoter. Therefore, we hypothesized that histone deacetylase inhibitors (HDACI) which are known to induce p21 expression in cancer cells might be effective on ES cells. HDACI inhibited ES cell growth via induction of p21 expression both in vitro and in vivo. However, a certain type of HDACI showed cross-resistance to the drug-resistant ES cells. Thus we should pay great attention to the resistance of ES cells to HDACIs in clinical trials. We also investigated the effects of the knockdown of EWS-Fli1 expression by siRNA on apoptosis induction in ES cells. The challenge of siRNA against EWS-Fli1 to ES cells did not induce apoptosis, but senescence in ES cells. This observation indicate the new function of EWS-Fli1, i.e., EWS-Fli1 might inhibit the induction of senescence in ES cells which might lead to the oncogenesis of ES. These results suggest that inhibition of these functions of EWS-Fli1 might promise the development of the molecular target therapy for the treatment of ES patients. Less

  • Research Products

    (32 results)

All 2006 2005

All Journal Article (29 results) Book (3 results)

  • [Journal Article] Involvement of P-glycoprotein and MRP1 in resistance to cyclic tetrapeptide subfamily of histone deacetylase inhibitors in the drug-resistant osteosarcoma and Ewing's sarcoma cells.2006

    • Author(s)
      Okada T, et al.
    • Journal Title

      Int.J.Cancer, 118(1)

      Pages: 90-97

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] DNA hypermethylation status of multiple genes in soft tissue sarcomas2006

    • Author(s)
      Kawaguti K, et al.
    • Journal Title

      Mod Pathol 19(1)

      Pages: 106-114

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] The possibule role of EWS-Flil in evasion of senescence in Ewing's family tumors2006

    • Author(s)
      Matunobu T, ei al.
    • Journal Title

      Cancer Res 66(22)

      Pages: 803-811

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Chromosomal and microsatellite instability of malignant peripheral nerve sheath tumors : The study of 10 tumors from 9 patients.2006

    • Author(s)
      Kobayashi C, et al.
    • Journal Title

      Cancer Genet Cytogen in press

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Aberrant expression of CHFR in malignant peripheral nerve sheath tumors2006

    • Author(s)
      Kobayashi C, et al.
    • Journal Title

      Mod.Pathol in press

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Involvement of P-glycoprotein and MRP1 in resistance to cyclic tetrapeptide subfamily of histone deacetylase inhibitors in the drug-resistant osteosarcoma and Ewing's sarcoma cells.2006

    • Author(s)
      Okada T, et al.
    • Journal Title

      Int.J.Cancer 118(1)

      Pages: 90-97

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] DNA hypermethylation status of multiple genes in soft tissue sarcomas2006

    • Author(s)
      Kawaguchi K, et al.
    • Journal Title

      Mod Pathol 19(1)

      Pages: 106-114

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] The possible role of EWS-Fli1 in evasion of senescence in Ewing's family tumors2006

    • Author(s)
      Matsunobu T, et al.
    • Journal Title

      Cancer Res. 66(2)

      Pages: 803-811

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Chromosomal and microsatellite instability of malignant peripheral nerve sheath tumors : The study of 10 tumors from 9 patients.2006

    • Author(s)
      Kobayashi C, et al.
    • Journal Title

      Cancer Genet Cytogen (in press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Aberrant expression of CHFR in malignant peripheral nerve sheath tumors2006

    • Author(s)
      Kobayashi C, et al.
    • Journal Title

      Mod.Pathol. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Microsatellite instability and hMLH1 and hMSH2 expression analysis soft tissue sarcomas2005

    • Author(s)
      Kawaguchi K, et al.
    • Journal Title

      Oncol.Rep., 13(2)

      Pages: 241-246

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Transactivation of cyclin E gene by EWS-Flil and antitumor effects of cyclin dependent kinase inhibitor on EWING's family tumor cells2005

    • Author(s)
      Li X, et al.
    • Journal Title

      Int.J.Cancer 116(3)

      Pages: 385-394

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Antitumor effects of histone deacetylase inhibitor on Ewing's family tumors.2005

    • Author(s)
      Sakimura R, et al.
    • Journal Title

      Int.J.Cancer 116(5)

      Pages: 784-792

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Intralesional fibrous septum in chordoma : a clinicopathologic and immunohistochemical study of 122 lesions.2005

    • Author(s)
      Naka T, et al.
    • Journal Title

      Am.J.Clin.Pathol., 124(2)

      Pages: 288-294

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Genetic and epigenetic alterations of the PTEN gene in soft tissue sarcomas2005

    • Author(s)
      Kawaguchi K, et al.
    • Journal Title

      Hum.Pathol., 36(4)

      Pages: 357-363

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] ATP-binding cassette superfamily transporter gene expression in human soft tissue sarcomas2005

    • Author(s)
      Oda Y, et al.
    • Journal Title

      Int.J.Cancer, 114(6)

      Pages: 854-862

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Histogenesis of intraregional fibrous septum in chordoma.2005

    • Author(s)
      Naka T, et al.
    • Journal Title

      Pathol.Res.Pract., 201(6)

      Pages: 443-447

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Alterations of the RB1 gene in dedifferentiated liposarcoma.2005

    • Author(s)
      Tkahira T, et al.
    • Journal Title

      Mod.Pathol., 18(11)

      Pages: 1461-1470

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Frequent alteration of p16(INK4a)/p14(ARF) and p53 pathways in the round cell component of myxoid/round cell liposarcoma : p53 gene alterations and reduced p14(ARF) expression both correlate with poor prognosis.2005

    • Author(s)
      Oda Y, et al.
    • Journal Title

      J Pathol. 207(4)

      Pages: 410-421

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Five-year evolution of a telangiectatic osteosarcoma initially managed as an aneurysmal bone cyst.2005

    • Author(s)
      Saito T, et al.
    • Journal Title

      Skeletal Radiol 34(5)

      Pages: 290-294

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Microsatellite instability and hMLH1 and hMSH2 expression analysis in soft tissue sarcomas2005

    • Author(s)
      Kawaguchi K, et al.
    • Journal Title

      Oncol.Rep. 13(2)

      Pages: 241-246

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Transactivation of cyclin E gene by EWS-Fli1 and antitumor effects of cyclin dependent kinase inhibitor on EWING's family tumor cells2005

    • Author(s)
      Li X, et al.
    • Journal Title

      Int.J.Cancer 116(3)

      Pages: 385-394

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Intralesional fibrous septum in chordoma : a clinicopathologic and immunohistochemical study of 122 lesions.2005

    • Author(s)
      Naka T, et al.
    • Journal Title

      Am.J.Clin.Pathol. 124(2)

      Pages: 288-294

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Genetic and epigenetic alterations of the PTEN gene in soft tissue sarcomas2005

    • Author(s)
      Kawaguchi K, et al.
    • Journal Title

      Hum.Pathol. 36(4)

      Pages: 357-363

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] ATP-binding cassette superfamily transporter gene expression in human soft tissue sarcomas2005

    • Author(s)
      Oda Y, et al.
    • Journal Title

      Int.J.Cancer 114(6)

      Pages: 854-862

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Histogenesis of intralesional fibrous septum in chordoma.2005

    • Author(s)
      Naka T, et al.
    • Journal Title

      Pathol.Res.Pract. 201(6)

      Pages: 443-447

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Alterations of the RB1 gene in dedifferentiated liposarcoma.2005

    • Author(s)
      Takahira T, et al.
    • Journal Title

      Mod.Pathol. 18(11)

      Pages: 1461-1470

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Frequent alteration of p16(INK4a)/p14(ARF) and p53 pathways in the round cell component of myxoid/round cell liposarcoma : p53 gene alterations and reduced p14(ARF) expression both correlate with poor prognosis.2005

    • Author(s)
      Oda Y, et al.
    • Journal Title

      J.Pathol. 207(4)

      Pages: 410-421

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Five-year evolution of a telangiectatic osteosarcoma initially managed as an aneurysmal bone cyst.2005

    • Author(s)
      Saito T, et al.
    • Journal Title

      Skeletal Radiol. 34(5)

      Pages: 290-294

    • Description
      「研究成果報告書概要(欧文)」より
  • [Book] 外来で見逃さない骨・軟部腫瘍ABC2005

    • Author(s)
      岩本幸英
    • Total Pages
      103
    • Publisher
      メジカルビュー社
    • Description
      「研究成果報告書概要(和文)」より
  • [Book] 整形外科Knack&Pitfalls骨・軟部腫瘍外科の要点と盲点2005

    • Author(s)
      岩本幸英
    • Total Pages
      320
    • Publisher
      文光堂
    • Description
      「研究成果報告書概要(和文)」より
  • [Book] 整形外科領域の腫瘍 : 悪性骨・軟部腫瘍に対する化学療法 癌化学療法update2005

    • Author(s)
      岩本幸英(分担執筆)
    • Total Pages
      524
    • Publisher
      中外医学社
    • Description
      「研究成果報告書概要(和文)」より

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Published: 2007-12-13  

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