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癌治療薬探索を目指した新規スプライシングモニタリングシステム構築への挑戦

Research Project

Project/Area Number 24659173
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeSingle-year Grants
Research Field Experimental pathology
Research InstitutionHokkaido University

Principal Investigator

田中 伸哉  北海道大学, 医学(系)研究科(研究院), 教授 (70261287)

Project Period (FY) 2012-04-01 – 2014-03-31
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywordsスプライシング / 薬剤スクリーニング / アダプター分子 / 癌
Research Abstract

本研究はこれまで全く未知であったmRNAのスプライシングに基づく発癌メカニズムを明らかにし、その治療薬を探索するシステムを構築することを目的とする。
具体的には多くのヒト癌の悪性化に関与することが判明しているシグナル伝達アダプター分子CRKに焦点をあて転移能の高いCRK-IIへの転換機構を明らかにする。CRKのスプライシングモニタリングシステムを構築し、CRKのスプライシングを制御する機構を分子レベルmicroRNAをスクリーニンし、これまでに全く未知のメカニズムを明らかにする。遺伝子発現は従来転写因子を中心とするエピジェネティックな解析が主流であり近年はmicroRNAが注目されているが、もう1つの重要なメカニズム1つであるスプライシング機構は解明が進んでおらず、疾患との関連、癌との関連では全く深い検討はなされていないのが現状である。
今回我々はシグナル伝達アダプター分子CRKがスプライシングバリアントにより機能が異なる点に着目し新規のスプライシングモニタリングシステムを構築するものであり、これまでにない時間空間的なスプライシング情報を得ることができ、正常細胞と癌細胞のスプライシングの差を明確にする画期的なシステムとなることが期待される。
本年度の研究においてヒトCRKゲノムをBACクローンより単離してその遺伝子配列を決定した。またCRKゲノムにGFPをN末端とC末端の2つの部分に分けて挿入し、スプライシングが生じるときにGFPの野生型の蛋白が発現するベクターをデザインした。またスプライシングによる生理作用をあらかじめ検討するためにCRK-IとCRK-IIをそれぞれ組み込んだ細胞を作成したところ、CRK-IIはepithelial mesenchymal transitionに積極的に関与することが明らかとなった。今後スプライシングとEMTの関連についても着目して研究を進める。

Report

(2 results)
  • 2013 Annual Research Report
  • 2012 Research-status Report
  • Research Products

    (23 results)

All 2013 2012

All Journal Article (15 results) (of which Peer Reviewed: 14 results) Presentation (8 results)

  • [Journal Article] Inhibition of GSH synthesis potentiates temozolomide-induced bystander effect in glioblastoma.2013

    • Author(s)
      Kohsaka, S.
    • Journal Title

      Cancer Letter

      Volume: 33 Issue: 1 Pages: 68-75

    • DOI

      10.1016/j.canlet.2012.12.005

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Downregulation of miRNA-31 induces taxane resistance in ovarian cancer cells through increase of receptor tyrosine kinase MET2013

    • Author(s)
      Takashi Mitamura
    • Journal Title

      Oncogenesis

      Volume: 2 Issue: 3 Pages: e40-e40

    • DOI

      10.1038/oncsis.2013.3

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Immunohistochemical molecular expression profile of metastatic brain tumor for potent personalized medicine.2013

    • Author(s)
      Kato Y, Nishihara H, Yuzawa S, Mohri H, Kanno H, Hatanaka Y, Kimura T, Tanino M, Tanaka S.
    • Journal Title

      Brain Tumor Pathol.

      Volume: 0 Pages: 0-0

    • NAID

      120005460237

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Clinicopathological evaluation of cyclooxygenase-2 expression in meningioma: immunohistochemical analysis of 76 cases of low and high-grade meningioma.2013

    • Author(s)
      Kato Y, Nishihara H, Mohri H, Kanno H, Kobayashi H, Kimura T, Tanino M, Terasaka S, Tanaka S.
    • Journal Title

      Brain Tumor Pathol.

      Volume: 0 Pages: 0-0

    • NAID

      120005537451

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Gene regulation of prominin-1 (CD133) in normal and cancerous tissues.2013

    • Author(s)
      K. Tabu, N. Bizen, T. Taga, and S. Tanaka
    • Journal Title

      Adv.Exp.Med.Biol.

      Volume: 777 Pages: 73-85

    • DOI

      10.1007/978-1-4614-5894-4_5

    • ISBN
      9781461458937, 9781461458944
    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] STAT3 inhibition overcomes temozolomide resistance in glioblastoma by downregulating MGMT expression.2012

    • Author(s)
      Kohsaka, S., Wang, L.,Yachi, K.,Mahabir, R.,Narita, T.,Itoh, T.,Tanino, M.,Kimura, T.,Nishihara H.,Tanaka, S.
    • Journal Title

      Mol Cancer Ther.

      Volume: 11 Pages: 1289-1299

    • NAID

      120005228738

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] CD133 negatively regulates tumorigenicity via AKT pathway in synovial sarcoma.2012

    • Author(s)
      Kimura, T.,Wang, L.,Tabu, K.,Nishihara, H.,Mashita, Y.,Kikuchi, N.,Tanino, M.,Hiraga, H.,Tanaka, S.
    • Journal Title

      Cancer invest

      Volume: 30 Pages: 390-397

    • NAID

      120005228733

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Prognostic implication of histological oligodendroglial tumor component: clinicopathological analysis of 111 cases of malignant gliomas.2012

    • Author(s)
      Kanno, H.,Nishihara, H.,Narita, T.,Yamaguchi, S.,Kobayashi, H.,Tanino, M.,Kimura, T.,Terasaka S.,Tanaka, S.
    • Journal Title

      PLoS One.

      Volume: 7

    • NAID

      120004650825

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] CRKL plays a pivotal role in tumorigenesis of head and neck squamous cell carcinoma through the regulation of cell adhesion.2012

    • Author(s)
      Yanagi, H.,Wang , L.,Nishihara, H.,Kimura, T.,Tanino, M.,Yanagi, T.,Fukuda, S.,Tanaka, S.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 418 Pages: 104-109

    • NAID

      120005183147

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Expression of O6-methylguanine DNA methyltransferase (MGMT) and immunohistochemical analysis of 12 pineal parenchymal tumors.2012

    • Author(s)
      Kanno, H.,Nishihara, H.,Oikawa, M.,Ozaki, Y.,Murata, J.,Sawamura, Y.,Kato, M.,Kubota, K.,Tanino, M. Kimura, T.,Nagashima, K.,Itoh, T.,Tanaka, S.
    • Journal Title

      Neuropathology

      Volume: 32 Issue: 6 Pages: 647-653

    • DOI

      10.1111/j.1440-1789.2012.01315.x

    • NAID

      120005356854

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Toll-like receptor 3 signaling converts tumor-supporting myeloid cells to tumoricidal effectors.2012

    • Author(s)
      Shime, H.,Matsumoto, M.,Oshiumi, H.,Tanaka, S.,Nakane, A.,Iwakura, Y.,Tahara, H.,Inoue, N.,Seya, T.
    • Journal Title

      Proc Natl Acad Sci U S A.

      Volume: 109 Pages: 2066-2071

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] TRIM67 negatively regulates Ras activity through degradation of 80K-H and induces neuritogenesis.2012

    • Author(s)
      Yaguchi, H.,Okumura, F.,Takahashi, H.,Kano, T.,Kameda, H.,Uchigashima, M.,Tanaka, S.,Watanabe, M. Sasaki, H.,Hatakeyama, S.
    • Journal Title

      J Biol Chem.,

      Volume: 287 Pages: 12050-12059

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] “CRK” Atlas of Genetics and Cytogenetics in Oncology and Haematology2012

    • Author(s)
      Shinya Tanaka.
    • Journal Title

      Atlas of Genetics and Cytogenetics in Oncology and Haematology

      Volume: 17p13.3 Pages: 1324647-1359561

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Roles for Crk in Cancer Metastasis and Invasion.2012

    • Author(s)
      Masumi Tsuda and Shinya Tanaka.
    • Journal Title

      Genes & Cancer

      Volume: 3 Issue: 5-6 Pages: 334-340

    • DOI

      10.1177/1947601912458687

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Regulation of MGMT and application for the therapy to attenuate the chemoresistance.2012

    • Author(s)
      Shinji Kohsaka, Hiromi Kanno, Shinya Tanaka.
    • Journal Title

      Nihon Rinsho

      Volume: 8 Pages: 346-352

    • Related Report
      2012 Research-status Report
  • [Presentation] 新規シグナル特異的阻害剤スクリーニングシステムを用いた膠芽腫治療薬の探索2013

    • Author(s)
      王磊、津田真寿美、菅野宏美、木村太一、谷野美智枝、西原広史、田中伸哉
    • Organizer
      第102回日本病理学会総会
    • Place of Presentation
      ロイトン札幌(北海道)
    • Related Report
      2013 Annual Research Report
  • [Presentation] 膠芽腫における分子標的治療薬耐性メカニズムの解明2013

    • Author(s)
      津田真寿美、王磊、谷野美智枝、木村太一、西原広史、田中伸哉
    • Organizer
      第102回日本病理学会総会
    • Place of Presentation
      ロイトン札幌(北海道)
    • Related Report
      2013 Annual Research Report
  • [Presentation] CrkI and CrkII Promote Epithelial - Mesenchymal Transition in A549 Lung Cancer Cell Line.2013

    • Author(s)
      Aiman Elmansuri, Mishie Tanino, Roshan Mahabir, Lei Wang, Masumi Tsuda, Taichi , Kimura, Hiroshi Nishihara, Shinya Tanaka.
    • Organizer
      第102回日本病理学会総会
    • Place of Presentation
      ロイトン札幌(北海道)
    • Related Report
      2013 Annual Research Report
  • [Presentation] ERC/Mesothelin is one of principle biomarkers for digestive cancer to predict patients’ prognosis (ERC/Mesothelinは消化器癌における重要な予後予測因子である)2013

    • Author(s)
      西原広史、樋野興夫、藤堂省、田中伸哉
    • Organizer
      第17回日本がん分子標的治療学会学術集会
    • Place of Presentation
      国立京都国際会館(京都)
    • Related Report
      2013 Annual Research Report
  • [Presentation] The distinct role of CRKI, CRKII and CRKL in tumorigenesis of human head and neck squamous cell carcinoma.2012

    • Author(s)
      Hiroshi Nishihara, Hiroko Yanagi, Yusuke Fukushima, Teruki Yanagi, Lei Wang, Taichi Kimura, Mishie Tanino, Masumi Tsuda and Shinya Tanaka.
    • Organizer
      Mechanisms & Models of Cancer Meeting
    • Place of Presentation
      Salk Institute(USA)
    • Related Report
      2012 Research-status Report
  • [Presentation] STAT3 inhibition overcomes temozolomide resistance in glioblastoma by downregulation of MGMT expression.2012

    • Author(s)
      Shinji Kohsaka, Lei Wang, Kazuhiro Yachi, Roshan Mahabir, Mishie Tanino, Taichi Kimura, Hiroshi Nishihara, Shinya Tanaka
    • Organizer
      Cold Spring Harbor Laboratory Meeting; Mechanisms and Models of Cancer
    • Place of Presentation
      Cold Spring Harbor(USA)
    • Related Report
      2012 Research-status Report
  • [Presentation] Irradiation Induced Glial-Mesenchaymal Transition in Malignant Glioma.2012

    • Author(s)
      Roshan Mahabir, Mishie Tanino, Aiman Elmansuri, Lei Wang, Taichi Kimura, Masumi Tsuda, Hiroshi Nishihara, Shinya Tanaka
    • Organizer
      第71回日本癌学会学術総会
    • Place of Presentation
      ロイトン札幌(北海道)
    • Related Report
      2012 Research-status Report
  • [Presentation] Involvement of CrkI and CrkII in epithelial – Mesenchymal Transition (EMT) and its Role in Lung Metastasis2012

    • Author(s)
      Elmansli Aiman, Mishie Tanino, Roshan Mahabir, Lei Wang, Taichi Kimura, Masumi Tsuda, Hiroshi Nishihara, Shinya Tanaka.
    • Organizer
      第71回日本癌学会学術総会
    • Place of Presentation
      ロイトン札幌(北海道)
    • Related Report
      2012 Research-status Report

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Published: 2013-05-31   Modified: 2019-07-29  

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