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β-catenin/Tcf複合体の新規転写標的分子の同定と大腸癌における機能解析

Research Project

Project/Area Number 18659380
Research Category

Grant-in-Aid for Exploratory Research

Allocation TypeSingle-year Grants
Research Field Digestive surgery
Research InstitutionKanazawa University

Principal Investigator

源 利成  Kanazawa University, がん研究所, 教授 (50239323)

Co-Investigator(Kenkyū-buntansha) 高橋 豊  千葉大学, 大学院・医学研究院, 教授 (10179541)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2006: ¥2,000,000 (Direct Cost: ¥2,000,000)
Keywords大腸癌 / シグナル伝達 / β-カテニン / CRD-BP / RNAトランス因子
Research Abstract

本研究は,細胞がん化プロセスにおけるユビキチンシステムの機能異常や調節障害の分子メカニズムとその帰結を明らかにすることにより,大腸発がん、進展の分子機構を新しい視点から解明するとともに,その成果をがんの分子診断や治療法の開発のための分子基盤として応用することを目指して計画した。
蛋白質ユビキチン化システムが細胞がん化へ能動的に関わるという着想から我々は,大腸癌においてWnt/β-カテニンシグナルによりそのmRNAが安定化され。発現誘導されるβ-TrCP(E3ユビキチン連結酵素)がβ-カテニンがん化シグナルとNF-kB細胞生存シグナルを統御することにより,がんの浸潤や転移を促進することを発見した。昨年度は,Wntシグナル依存的なβ-TrCP mRNAの安定化と発現誘導に作用するβ-カテニン/Tcf複合体の新規転写標的分子CRD-BP(coding region determinant-binding protein)を同定した。
CRD-BPはRNAトランス因子で,Wntシグナルに応答して大腸癌細胞で過剰発現する結果,c-mycやIGF-IIのmRNAを安定化することにより複数の細胞生存、増殖経路(Wnt/β-カテニン,NF-kB,c一Myc,IGF-II)を統括すると想定し,今年度は臨床的な大腸癌症例の解析に着手した。従来から進めてきた大腸癌臨床検体の集積を継続し,臨床病理学的データや術後経過を調査してバンク化した。そして,これらの症例の癌組織におけるCRD-BPの発現と局在を,β-カテニン,β-TrCP,NF-kB(p65活性型サプエ=ット),c-Mycなどと比較解析した。実際のがんにおけるCRD-BPの病的作用を明らかにするために現在,大腸癌におけるこれらの分子の発現変動と,浸潤,転移,再発などを含むが布病態や担がん症例の生命予後との関連について解析を進めている。

Report

(2 results)
  • 2007 Annual Research Report
  • 2006 Annual Research Report
  • Research Products

    (24 results)

All 2008 2007 2006

All Journal Article (11 results) (of which Peer Reviewed: 5 results) Presentation (13 results)

  • [Journal Article] Low expression of gamma glutamyl hydrolase mRNA in pimary colorectal cancer with the CpG island methvlator phenotype.2008

    • Author(s)
      Kawakami K, et. al., Minamoto T.
    • Journal Title

      British Journal of Cancer (印刷中)(掲載確定)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Adjuvant immunochemotherapy with protein-bound polysaccharide K for colon cancer in relation to oncogenic β-catenin activation.2007

    • Author(s)
      Yamashita K, Takahashi Y., et. al., Minamoto T.
    • Journal Title

      Diseases of the Colon & Rectum 50

      Pages: 1169-81

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inhibition of GSK-3β activity attenuates proliferation of human colon cancer cells in rodents.2007

    • Author(s)
      Shakoori A, et. al., Takahashi Y, Kawakami K, Minamoto T.
    • Journal Title

      Cancer Science 98

      Pages: 1388-93

    • NAID

      10019998582

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Methylation levels of LINE-1 repeats and CpG island loci are inversely related in normal colonic mucosa.2007

    • Author(s)
      Iacopetta B, et. al., Minamoto T. Kawakami K
    • Journal Title

      Cancer Science 98

      Pages: 1454-60

    • NAID

      10019998960

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Adjuvant immunochemotherapy with protein-bound polysaccharide K for colon cancer in elation to oncogenic β-catenin activation.2007

    • Author(s)
      Yamashita K, et al., Takahashi Y, Minamoto T
    • Journal Title

      Diseases of the Colon and Rectum 50

      Pages: 1-13

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Detection of active fraction of GSK3β in cancer cells by non-radioisotopic in vitro kinase assay.2007

    • Author(s)
      Mai W, Takahashi Y, Kawakami K, Minamoto T
    • Journal Title

      Oncology (印刷中)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Detection of active fraction of GSK3β in cancer cells by nonladioisotopic invitro kinase assay.2006

    • Author(s)
      Mai W, et. al., Takahashi Y, Kawakami K, Minamoto T.
    • Journal Title

      Oncology(註:2007年7月に掲載) 71

      Pages: 297-305

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] c-kit gene mutation is common and widely distributed in intracranial germinomas.2006

    • Author(s)
      Kamakura Y, Minamoto T, et al.
    • Journal Title

      Journal of Neurosurgery 104・3 Suppl

      Pages: 173-180

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Effect of gemcitabine on the expression of apoptosis-related genes in human pancreatic cancer cells.2006

    • Author(s)
      Jiang PH, et al., Minamoto T
    • Journal Title

      World Journal of Gastroenterology 12・10

      Pages: 1597-1602

    • NAID

      120000807303

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Loss of imprinting in IGF2 in colorectal carcinoma assessed by microdissection.2006

    • Author(s)
      Maenaka S, Minamoto T, et al.
    • Journal Title

      Oncology Report 15・4

      Pages: 791-795

    • Related Report
      2006 Annual Research Report
  • [Journal Article] CRD-BP mediates stabilization of βTrCP1 and c-myc mRNA in response to β-catenin signaling.2006

    • Author(s)
      Noubissi F, Minamoto T, et al.
    • Journal Title

      Nature 441・7095

      Pages: 898-901

    • Related Report
      2006 Annual Research Report
  • [Presentation] Combined effect of gemcitabine and GSK3β inhibitor against pancreatic cancer resulting in altered gene expression profiles.2007

    • Author(s)
      Shimasaki T, Kawakami K, Minamoto T, et. al.
    • Organizer
      The Second Meeting of Asian-Oceanic Pancreatic Association (AOPA)
    • Place of Presentation
      神戸
    • Year and Date
      2007-10-18
    • Related Report
      2007 Annual Research Report
  • [Presentation] Deregulated GSK3β activity in colorectal cancer: its association with tumorcell survival and proliferation.2007

    • Author(s)
      Minamoto T, et. al., Takahashi Y, Kawakami K.
    • Organizer
      Annual Meeting 2007 of the American Association for Cancer Research
    • Place of Presentation
      アメリカ合衆国ロサンジェルス
    • Related Report
      2007 Annual Research Report
  • [Presentation] mRNA expression of gamma glutamyl hydrolase (GGH) is negatively associated with DNA methylation status in primary colorectal cancer.2007

    • Author(s)
      Kawakami K, Minamoto T, et. al.
    • Organizer
      Annual Meeting 2007 of the American Association for Cancer Research
    • Place of Presentation
      アメリカ合衆国ロサンジェルス
    • Related Report
      2007 Annual Research Report
  • [Presentation] 塩酸ゲムシタビンとGSK3β阻害薬の膵癌細胞への抗腫瘍効果とその分子機構.2007

    • Author(s)
      島崎 猛夫, 源 利成, ほか.
    • Organizer
      第38回日本膵臓学会大会
    • Place of Presentation
      福岡
    • Related Report
      2007 Annual Research Report
  • [Presentation] Wntシグナル制御破綻に関わる新しい分子細胞機構の解明と大腸がん制御への展開.2007

    • Author(s)
      源 利成, ほか 高橋 豊, 川上 和之.
    • Organizer
      第62回日本消化器外科学会定期学術集会
    • Place of Presentation
      東京
    • Related Report
      2007 Annual Research Report
  • [Presentation] Inhibition of glycogen synthase kinase 3β (GSK3β) attenuates proliferation of human colon cancer cells in rodents.2007

    • Author(s)
      Minamoto T, et. al., Takahashi Y, Kawakami K.
    • Organizer
      第66回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Related Report
      2007 Annual Research Report
  • [Presentation] Methylation level of LINE-1 repeats as a prognostic factor for the patients with colorectal cancer.2007

    • Author(s)
      Kawakami K, et. al., Minamoto T.
    • Organizer
      第66回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Related Report
      2007 Annual Research Report
  • [Presentation] Synergistic effect of gemcitabine and GSK3β inhibitors against human pancreas cancer:GSK3β as a new therapeuutic target.2007

    • Author(s)
      Shimasaki T, Kawakami K, Minamoto T, et. al.
    • Organizer
      第66回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Related Report
      2007 Annual Research Report
  • [Presentation] Inhiition of synthase kinase 3β (GSK3β) in glioblastoma attenuates tumor cells'viability and induces apoptosis depending on p53.2007

    • Author(s)
      Miyashita K, et. al., Kawakami K, Minamoto T.
    • Organizer
      第66回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Related Report
      2007 Annual Research Report
  • [Presentation] Expression,deregulated activity and pathologic role of GSK3β in gastrointestinall,pancreas and liver cancers.2007

    • Author(s)
      Mai W, et. al., Kawakami K, Minamoto T.
    • Organizer
      第66回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Related Report
      2007 Annual Research Report
  • [Presentation] 消化器がんの新しい治療標的GSK3βの発現,活性,機能解析.2007

    • Author(s)
      川上 和之, ほか, 高橋 豊, 源 利成.
    • Organizer
      第18回日本消化器がん発生学会総会
    • Place of Presentation
      札幌
    • Related Report
      2007 Annual Research Report
  • [Presentation] 膵癌に対する塩酸ゲムシタビンとGSK3β阻害剤併用の抗腫瘍効果とその分子機構.2007

    • Author(s)
      島崎 猛夫, 川上 和之, 源 利成, ほか.
    • Organizer
      第18回日本消化器がん発生学会総会
    • Place of Presentation
      札幌
    • Related Report
      2007 Annual Research Report
  • [Presentation] Synergistic effect of gemcitabine and GSK3β inhibitor against human pancreas cancer:GSK3β as a new therapeutic molecular target.2007

    • Author(s)
      Shimasaki T, Kawakami K, Minamoto T, et. al.
    • Organizer
      Annual Meeing of American Pancreatic Association
    • Place of Presentation
      アメリカ合衆国シカゴ
    • Related Report
      2007 Annual Research Report

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Published: 2006-04-01   Modified: 2016-04-21  

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