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インスリン様増殖因子系を標的とする消化器癌の発癌進展機構の解明と遺伝子治療

Research Project

Project/Area Number 14704030
Research Category

Grant-in-Aid for Young Scientists (A)

Allocation TypeSingle-year Grants
Research Field Gastroenterology
Research InstitutionSapporo Medical University

Principal Investigator

山本 博幸  札幌医科大学, 医学部, 助手 (40332910)

Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000)
Fiscal Year 2003: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
Fiscal Year 2002: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywords消化器癌 / IGF / IGI-Iレセプター / loss of imprinting / マトリライシン / proprotein convertase / dominant negative / 分子標的治療法 / protein array / 浸潤先進部 / Akt / アデノウイルス
Research Abstract

消化器癌の発癌進展におけるインスリン様増殖因子(IGF)及びそのレセプターであるIGF-IRの役割について系統的に解析した。IGF-IIの発現亢進機構としてloss of imprintingの重要性を明らかにした。また、マトリライシンがIGFBP-3 proteaseとして機能し、IGFシグナルの亢進に深く関わっていることを明らかにした。Pro-IGF-IRからIGF-IRへの変換に重要なproprotein convertaseの発現亢進も明らかにした。さらに、ヒト膵臓癌細胞株においてIGF-IR dominant negative(IGF-IR/dn)によるIGF-IR阻害が下流のシグナル伝達に及ぼす影響ならびにIGF-IR/dnの腹膜播種モデルにおける抗腫瘍効果を検討した。膜貫通ドメインと細胞外ドメインを保持するIGF-IR/dnに比べ、細胞外成分のみからなる分泌型のIGF-IR/dnは、より強い抗腫瘍効果を示し、bystander効果が示唆された。IGF-IR/dnによる増殖抑制効果は主としてPI3-K/Akt系を介して、一方、アポトーシスの誘導は主にPI3-K/Akt系とp38系の両者を介して発揮されていると考えられた。IGF-IR/dnは、腹膜播種モデルにおいてリンパ節転移数と肝転移数を減じ、マウスの生存期間を有意に延長した。従って、IGF-IR/dnは膵臓がんの有望な分子標的治療法と成りえることが示唆された。大腸癌、胃癌においても同様の成果を得つつあり、研究全体を通して、消化器癌の発癌進展におけるインスリン様増殖因子系の重要性および治療の標的としての有用性を示すことができた。

Report

(2 results)
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] Hiroyuki Yamamoto: "Association of trypsin expression with tumor progression and matrilysin expression in human colorectal cancer"Journal of Pathology. 199. 176-184 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yongfen Min: "Genetic blockade of the insulin-like growth factor-I receptor : a promising strategy for human pancreatic cancer"Cancer Research. 63. 6432-6441 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hiroyuki Yamamoto: "Expression of ets-related transcriptional factor E1AF is associated with tumor progression and overexpression of matrilysin in human gastric cancer"Carcinogenesis. 25. 325-332 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shina Horiuchi: "Association of Ets-related transcriptional factor E1AF expression with tumor progression and overexpression of MMP-1 and matrilysin in human colorectal cancer"Journal of Pathology. 200. 568-576 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Keiki Matsuno: "Matrix metal loproteinase matrilysin expression represents the degree of inflammation in ulcerative colitis"Journal of Gastroenterology. 38. 348-354 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yasushi Adachi: "Dominant negative IGF-I receptor"Nippon Rinsho. 61. 500-504 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hiroyuki Yamamoto: "Association of trypsin expression with tumor progression and matrilysin expression in human colorectal cancer"Journal of Pathology. 199. 176-184 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hiroyuki Yamamoto: "Analysis of gene expression of human colorectal cancer tissues by cDNA array"Journal of Gastroenterology. 37. 83-86 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hiroyuki Yamamoto: "Matrix metalloproteinase matrilysin in the progression of cancers of the digestive organs"Research Advances in Cancer. 2. 121-129 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hiroyuki Yamamoto: "Gastrointestinal cancer of the microsatellite mutator phenotype pathway"Journal of Gastroenterology. 37. 153-163 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hiroaki Takahashi: "Mucin phenotype and microsatellite instability in multiple early gastric cancers"International Journal of Cancer. 100. 419-424 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hiroyuki Yamamoto: "Differential involvement of the hypermethylator phenotype in hereditary and sporadic colorectal cancers with high-frequency microsatellite instability"Genes, Chromosomes and Cancer. 33. 322-325 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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