2001 Fiscal Year Annual Research Report

EWS-Fli1融合遺伝子を指標としたEwing肉腫、PNETの診断、治療の研究

Research Project

Project/Area Number	10307034
Research Institution	KYUSHU UNIVERSITY
Principal Investigator	岩本幸英九州大学, 大学院・医学研究院, 教授 (00213322)
Co-Investigator(Kenkyū-buntansha)	田仲和宏九州大学, 医学部・附属病院, 助手 (10274458) 小田義直九州大学, 大学院・医学研究院, 講師 (70291515)
Keywords	Ewing肉腫 / PNET / EWS-Fli1 / 融合遺伝子 / 分子標的
Research Abstract	Ewing肉腫(ES)およびPNETは骨軟部悪性腫瘍の中で最も予後不良な腫瘍であり、90%以上の症例で特異的染色体転座t(11:22)がみられる。この転座の結果、異常な融合遺伝子EWS-Fli1が生じ、ES/PNETのがん化の原因そのものと考えられている。我々は、ES/PNET細胞株を用いEWS-Fli1融合遺伝子発現と増殖能との間に正の相関があり、EWS-Fli1融合遺伝子はES/PNETの癌化のみならず、その生物学的性質をも規定している可能性があることを示してきた。これらの結果をふまえ、本研究の目的は、EWS-Fli1融合遺伝子によって誘導される標的遺伝子を調べること、臨床検体におけるEWS-Fli1とその標的遺伝子の発現が臨床的パラメータと相関があるかを検証すること、である。ES/PNET細胞をEWS-Fli1に対するantisense oligonucleotideで処理すると増殖が阻害され、細胞周期のG1期に停止することから、antisense oligonucleotide処理前後の細胞からmRNAを抽出し、subtraction cloningおよびcDNA microarrayによって、発現の変化する遺伝子群をクローニングした。この内、EWS-Fli1の標的と考えられる遺伝子として、G1/S期移行に重要であるサイクリンDおよびEとE2F1、そのinhibitorであるp21およびp27を同定した。これらの遺伝子のプロモーター領域を解析した結果、P21プロモーターにEWS-Fli1が直接結合し、その発現を抑制することが明らかとなった。また、p27について臨床サンプルを用いて、発現の有無と予後との相関を調べた。その結果、P27発現が低レベルである群は、高発現群に比して有意に予後が不良であることが判明した。本研究は、EWS-Fli1の標的遺伝子の発現と臨床的予後が相関することを世界で初めて示したものである。

Research Products
(21 results)

All Other

All Publications (21 results)

[Publications] Mtsumoto, Y., et al.: "Small GTP-binding Protein, Rho, Both Increased and Decreased Cellular Motility, Activation of Matrix Metalloproteinase 2 and Invasion of Human Osteosarcoma Cells"Jpn.J.Cancer Res.. 92. 429-438 (2001)
[Publications] Matsumoto Y., et al.: "Downregulation and forcec expression of EWS-Fli1 fusion genereselts in changes in the expression of E(1)regulatory genes"Brit.J.Cancer. 84. 768-775 (2001)
[Publications] Saito T, et al.: "Expression of intercellular adhesion molecules in epithelioid sarcoma and malignant rhabodoid tumor"Pathol.Int.. 51. 532-542 (2001)
[Publications] Oda Y, et al.: "Pleomorphic Leiomyosarcoma-Clinicopathologic and immuno histochemical study with special emphasis on its distinction from ordinary leiomyosarcoma and malignant fibros histiocytoma"Am.J.Surg.Pathol.. 25. 1030-1038 (2001)
[Publications] Saito T, et al.: "β-catein nuclear expression correlates with cyclin DI over expression in sporadic desmoid tumors"J.Pathol.. 195. 222-228 (2001)
[Publications] Naka T, et al.: "Immuno histochemical analysis of E-cadherin, alpha-, beta-, gamma-cetenins, and neural cell adhesion molecule(NCAM)in chordoma"J.Clin.Pathol.. 54. 945-950 (2001)
[Publications] Sakamoto A, et al.: "H-ras oncogene mutation in dedifferentiated liposarcoma : Polymerase chain reaction-restriction fragment length polymorphism analysis"Am.J.Clin.Pathol.. 115. 235-242 (2001)
[Publications] Sito T, et al.: "E-Cadherin Gene Mutotions Frequently Occurin Synovial Sarcoma as a Determinant of Histologica Features"Am.J.Pathol.. 159. 2117-2124 (2001)
[Publications] Sakamoto A, et al.: "Immuno expression of Neurofibromin, S-100 Protein and Leu-7, and Mutation Analysis of the NF1 Gene at Codon 1423 in Osteofibros Dysplasia"Hum.Pathol.. 32. 1245-1251 (2001)
[Publications] Sakamoto A, et al.: "H-, K-and N-ras Gene Mutation Atypical Fibroxanthoma and Malignant fibrous Histiocytoma"Hum.Pathol.. 32. 1225-1231 (2001)
[Publications] Sakamoto A, et al.: "Immuno expression of ultraviolet photoproducts and p53 mutation analysis in atypical fibroxanthoma and superficial malignant fibrous histiocytoma"Mod.Pathol.. 14. 581-588 (2001)
[Publications] Sakamoto A, et al.: "H-ras oncogene mutation in dedifferentiated chondrosarcoma : Polymerase chain reaction-restriction fragment lengt polymorphism analysis of paraffin-embedded tissues"Mod.Pathol.. 14. 343-349 (2001)
[Publications] oda Y, et al.: "Secondary malignant giant-cell tumor of bone. Molecular abnormalities of p53 and H-ras gene correlated with malignant transformation"Histopathology. 39. 629-637 (2001)
[Publications] Kinoshita Y, et al.: "Mutation of the p53 gene mutations in malignant rhabdoidtumors of soft part and kidney : Immunohistochemical and DNA direct sequence analysis"J.Cancer Res.Clin.Oncol.. 127. 351-358 (2001)
[Publications] Shiratsuchi H, et al.: "Cytokeratin subunits of inclusion bodies in rhabdoid cells : Immunohistochemidal and clinicopathological study of malignant rhabdoid tumor and epithelioid sarcoma"Int.J.Surg.Pathol.. 9. 37-48 (2001)
[Publications] Miyajima K, et al.: "Relative quantitation of p53 and MDM2 gene expression in leiomyosarcoma ; rear-time semi-quantitative reverse transcription-polymerase chain reaction"Cancer Letters. 164. 177-188 (2001)
[Publications] Watanabe T, et al.: "Malignantperipheralnervesheathtumorarising within neurofibroma.An immunohistochemical analysis in the comparison between benign and malignant componcnts"J.Clin.Pathol.. 54. 631-636 (2001)
[Publications] Adachi T, et al.: "Adachi T, Oda Y, Sakamoto A, SaitoT, Tamiya S, Masuda K, Tsuneyoshi MImmunoreactivily of p53, mdrn2 and p21/WAF1 in dedifferentiated liposarcoma : special emphasis on the distinct immunophenotype of the Welldifferentiated component"Int.J.Surg.Pathol.. 9. 99-109 (2001)
[Publications] 岩本幸英(分担執筆): "今日の治療指針-2001年度版-私はこうして治療している-"医学書院. 1566 (2001)
[Publications] 幡广谷勝三, 岩本幸英(分担執筆): "今日の処方, 第3版"南江堂. 935 (2001)
[Publications] 松田秀一, 岩本幸英(分担執筆): "新OS NOW新世代の整形外科手術, No.13高齢者に対する整形外科手術-より高い機能を求めて"Medical View社. 192 (2001)

2001 Fiscal Year Annual Research Report

EWS-Fli1融合遺伝子を指標としたEwing肉腫、PNETの診断、治療の研究

Principal Investigator

岩本 幸英 九州大学, 大学院・医学研究院, 教授 (00213322)

Research Products

[Publications] Mtsumoto, Y., et al.: "Small GTP-binding Protein, Rho, Both Increased and Decreased Cellular Motility, Activation of Matrix Metalloproteinase 2 and Invasion of Human Osteosarcoma Cells"Jpn.J.Cancer Res.. 92. 429-438 (2001)

[Publications] Matsumoto Y., et al.: "Downregulation and forcec expression of EWS-Fli1 fusion genereselts in changes in the expression of E(1)regulatory genes"Brit.J.Cancer. 84. 768-775 (2001)

[Publications] Saito T, et al.: "Expression of intercellular adhesion molecules in epithelioid sarcoma and malignant rhabodoid tumor"Pathol.Int.. 51. 532-542 (2001)

[Publications] Oda Y, et al.: "Pleomorphic Leiomyosarcoma-Clinicopathologic and immuno histochemical study with special emphasis on its distinction from ordinary leiomyosarcoma and malignant fibros histiocytoma"Am.J.Surg.Pathol.. 25. 1030-1038 (2001)

[Publications] Saito T, et al.: "β-catein nuclear expression correlates with cyclin DI over expression in sporadic desmoid tumors"J.Pathol.. 195. 222-228 (2001)

[Publications] Naka T, et al.: "Immuno histochemical analysis of E-cadherin, alpha-, beta-, gamma-cetenins, and neural cell adhesion molecule(NCAM)in chordoma"J.Clin.Pathol.. 54. 945-950 (2001)

[Publications] Sakamoto A, et al.: "H-ras oncogene mutation in dedifferentiated liposarcoma : Polymerase chain reaction-restriction fragment length polymorphism analysis"Am.J.Clin.Pathol.. 115. 235-242 (2001)

[Publications] Sito T, et al.: "E-Cadherin Gene Mutotions Frequently Occurin Synovial Sarcoma as a Determinant of Histologica Features"Am.J.Pathol.. 159. 2117-2124 (2001)

[Publications] Sakamoto A, et al.: "Immuno expression of Neurofibromin, S-100 Protein and Leu-7, and Mutation Analysis of the NF1 Gene at Codon 1423 in Osteofibros Dysplasia"Hum.Pathol.. 32. 1245-1251 (2001)

[Publications] Sakamoto A, et al.: "H-, K-and N-ras Gene Mutation Atypical Fibroxanthoma and Malignant fibrous Histiocytoma"Hum.Pathol.. 32. 1225-1231 (2001)

[Publications] Sakamoto A, et al.: "Immuno expression of ultraviolet photoproducts and p53 mutation analysis in atypical fibroxanthoma and superficial malignant fibrous histiocytoma"Mod.Pathol.. 14. 581-588 (2001)

[Publications] Sakamoto A, et al.: "H-ras oncogene mutation in dedifferentiated chondrosarcoma : Polymerase chain reaction-restriction fragment lengt polymorphism analysis of paraffin-embedded tissues"Mod.Pathol.. 14. 343-349 (2001)

[Publications] oda Y, et al.: "Secondary malignant giant-cell tumor of bone. Molecular abnormalities of p53 and H-ras gene correlated with malignant transformation"Histopathology. 39. 629-637 (2001)

[Publications] Kinoshita Y, et al.: "Mutation of the p53 gene mutations in malignant rhabdoidtumors of soft part and kidney : Immunohistochemical and DNA direct sequence analysis"J.Cancer Res.Clin.Oncol.. 127. 351-358 (2001)

[Publications] Shiratsuchi H, et al.: "Cytokeratin subunits of inclusion bodies in rhabdoid cells : Immunohistochemidal and clinicopathological study of malignant rhabdoid tumor and epithelioid sarcoma"Int.J.Surg.Pathol.. 9. 37-48 (2001)

[Publications] Miyajima K, et al.: "Relative quantitation of p53 and MDM2 gene expression in leiomyosarcoma ; rear-time semi-quantitative reverse transcription-polymerase chain reaction"Cancer Letters. 164. 177-188 (2001)

[Publications] Watanabe T, et al.: "Malignantperipheralnervesheathtumorarising within neurofibroma.An immunohistochemical analysis in the comparison between benign and malignant componcnts"J.Clin.Pathol.. 54. 631-636 (2001)

[Publications] 岩本幸英(分担執筆): "今日の治療指針-2001年度版-私はこうして治療している-"医学書院. 1566 (2001)

[Publications] 幡广谷勝三, 岩本幸英(分担執筆): "今日の処方, 第3版"南江堂. 935 (2001)

[Publications] 松田秀一, 岩本幸英(分担執筆): "新OS NOW新世代の整形外科手術, No.13高齢者に対する整形外科手術-より高い機能を求めて"Medical View社. 192 (2001)

岩本幸英九州大学, 大学院・医学研究院, 教授 (00213322)