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肺癌の癌遺伝子ASH1およびCLCP1の機能解析

Research Project

Project/Area Number 18012057
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionAichi Cancer Center Research Institute

Principal Investigator

長田 啓隆  Aichi Cancer Center Research Institute, 分子腫瘍学部, 室長 (30204176)

Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥8,900,000 (Direct Cost: ¥8,900,000)
Fiscal Year 2007: ¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 2006: ¥4,400,000 (Direct Cost: ¥4,400,000)
Keywords肺がん / 神経内分泌分化 / 転移 / ヒストン修飾 / 肺癌 / 細胞分化
Research Abstract

神経内分泌分化肺癌は小細胞癌や一部の大細胞癌からなる高悪性度肺癌であり,この細胞分化と癌悪性化との関連が注目されている。神経内分泌分化肺癌の生存と増殖が,神経内分泌分化の規定因子ASHIの構成的発現に依存性を示すことを報告した。更に,このASH1の機能解析を進めたところ,ASHIが神経内分泌分化を誘導すると共に,培養下での足場非依存性増殖の促進や,移植腫瘍での増殖促進・組織型の変化を誘導することが判明した。又,その分子機序として,ASHIがE-カドヘリンやWntシグナル抑制因子DKK1等の癌抑制遺伝子の発現を抑制し,βーカテニン経路の活性化を誘導することを見出した。実際の肺癌検体の遺伝子発現プロファイルの検討から,これらASH1で発現抑制される遺伝子群は,小細胞肺癌で高頻度に発現低下しており,実際の神経内分泌分化肺癌の発症に関与することが示唆された。このASHIによる遺伝子発現抑制の分子機序を検討したところ,転写抑制性の修飾であるピストンH3の脱アセチル化とK27メチル化がプロモーター領域に誘導されることが判明し,又,ASHlとHDAC分子との結合も確認され,ASH1がHDACを標的遺伝子領域にリクルートしヒストン脱アセチル化を誘導し,発現抑制していると考えられた。更にH3K27メチル化についてChIP-on-chip解析にて,網羅的に検討したところ,ASH1により発現抑制される遺伝子群ほぼ全てでH3K27メチル化修飾が誘導され,ASHIがH3K27メチル化を介して発現制御することが強く示唆された。又,ASHIの標的遺伝子群の中で,ASHIにより誘導される細胞間接着の低下を担う新規遺伝子を同定し,新たな癌抑制遺伝子候補と考え,更に詳細を解析中である。転移関連がん遺伝子CLCPlに関しても,細胞運動能を促進し,SEMA4Bにより制御されることを報告し,更に検討を進めている。

Report

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

    (26 results)

All 2008 2007 2006 Other

All Journal Article (20 results) (of which Peer Reviewed: 9 results) Presentation (4 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Roles of achaete-scute homologue 1 in DKKI and E-cadherinr epression andneuroendocrine differentiation in lung cancer2008

    • Author(s)
      Osada H, et. al.
    • Journal Title

      Cancer Research 68

      Pages: 1647-55

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CLCPI interacts with semaphorin 4B and regulates motility of lung cancer cells2007

    • Author(s)
      Nagai H, et. al.
    • Journal Title

      Oncogene 26

      Pages: 4025-31

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Apoptosis induction by antisense oligonucleotides against miR-17-5p and miR-20a in lung cancers overexpressing miR-17-92.2007

    • Author(s)
      Matsubara H, et. al.
    • Journal Title

      Oncogene 26

      Pages: 6099-105

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Identification of a metastasis signature and the DLX4 homeobox proteinas a regulator of metastasis by combined transcriptome approach.2007

    • Author(s)
      Tomida S, et. al.
    • Journal Title

      Oncogene 26

      Pages: 4600-8

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel NBSI heterozygous germ line mutation causing MRE11-binding domainloss predisposes to common types of cancer.2007

    • Author(s)
      Ebi H, et. al.
    • Journal Title

      Cancer Research 67

      Pages: 11158-11165

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Lineage-specific dependency of lung adenocarcinomas on the lungdevelopment regulator TTF-1.2007

    • Author(s)
      Tanaka H, et. al.
    • Journal Title

      Cancer Research 67

      Pages: 6007-6011

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Human DREF regulates cell proliferation and ribosomal protein genes.2007

    • Author(s)
      Yamashita D, et. al.
    • Journal Title

      Mol.Cell.Biol 27

      Pages: 2003-13

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] RhoB is frequently downregulated in non-small-cell lung cancer and residesin the 2p24 homozygous deletion region of a lung cancer cell line.2007

    • Author(s)
      Sato N, et. al.
    • Journal Title

      Int.J.Cancer 120

      Pages: 543-51

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Alterations of DNA methylation and histone modifications contribute togene silencing in hepatocellular carcinomas.2007

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

      Hepatol Research 37

      Pages: 974-983

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] MicroRNAs in Biological and Carcinogenic Processes.2007

    • Author(s)
      Osada H, et. al.
    • Journal Title

      Carcinogenesis 28

      Pages: 2-12

    • Related Report
      2007 Annual Research Report
  • [Journal Article] Apoptosis induction by antisense oligonucleotides against miR-17-5p and miR-20a in lung cancers overexpressing miR-17-92.2007

    • Author(s)
      Matsubara H. et al.
    • Journal Title

      Oncogene (in press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Identification of a metastasis signature and the DLX4 homeobox protein as a regulator of metastasis by combined transcriptome approach.2007

    • Author(s)
      Tomida S. et al.
    • Journal Title

      Oncogene (in press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells.2007

    • Author(s)
      Nagai H. et al.
    • Journal Title

      Oncogene (in press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] hDREF regulates cell proliferation and expression of ribosomal protein genes.2007

    • Author(s)
      Yamashita D. et al.
    • Journal Title

      Molecular and Cellular Biology 27・6

      Pages: 2003-2013

    • Related Report
      2006 Annual Research Report
  • [Journal Article] RhoB is frequently downregulated in non-small-cell lung cancer and resides in the 2p24 homozygous deletion region of a lung cancer cell line.2007

    • Author(s)
      Sato N.et al.
    • Journal Title

      International Journal of Cancer 120・3

      Pages: 543-551

    • Related Report
      2006 Annual Research Report
  • [Journal Article] MicroRNAs in biological processes and carcinogenesis.2007

    • Author(s)
      Osada H. et al.
    • Journal Title

      Carcinogenesis 28・1

      Pages: 2-12

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Interaction of GATA-3/T bet transcription factors regulates expression of sialyl Lewis X homing receptors on Th1/Th2 lymphocytes2006

    • Author(s)
      Chen G-Y et al.
    • Journal Title

      Proc Natl Acad Sci U S A. 103(45)

      Pages: 16894-16899

    • Related Report
      2006 Annual Research Report
  • [Journal Article] EGFR point mutation in non-small cell lung cancer is occasionally accompanied by a second mutation or amplification.2006

    • Author(s)
      Yokoyama T. et al.
    • Journal Title

      Cancer Science 97・8

      Pages: 753-759

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Expression profile-defined classification of lung adenocarcinoma shows close relationship with underlying major genetic changes and clinicopathologic behaviors.2006

    • Author(s)
      Takeuchi T. et al.
    • Journal Title

      Journal of Clinical Oncology 24・11

      Pages: 1679-1688

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Altered regulation of c-jun and its involvement in anchorage-independent growth of human lung cancers.2006

    • Author(s)
      Maeno K. et al.
    • Journal Title

      Oncogene 25・2

      Pages: 271-277

    • Related Report
      2006 Annual Research Report
  • [Presentation] 神経内分泌分化誘導因子ASH1によるWntシグナル抑制因子DKK1の発現抑制2007

    • Author(s)
      長田 啓隆、他
    • Organizer
      第30回日本分子生物学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2007-12-13
    • Related Report
      2007 Annual Research Report
  • [Presentation] シンポジウム肺癌の分子生物学と治療の進歩:神経内分泌分化肺癌におけるASHI遺伝子の機能2007

    • Author(s)
      長田 啓隆、他
    • Organizer
      第66回 日本癌学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2007-10-04
    • Related Report
      2007 Annual Research Report
  • [Presentation] ASH1 gene may be prototypic "lineage-survival oncogene"and specific therapeutic target for lung cancers with neuroendocrine features.2007

    • Author(s)
      Osada H, et. al.
    • Organizer
      第13回日本遺伝子治療学会
    • Place of Presentation
      名古屋
    • Year and Date
      2007-06-29
    • Related Report
      2007 Annual Research Report
  • [Presentation] CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells.2007

    • Author(s)
      Osada H, et. al.
    • Organizer
      AACR annual meeting
    • Place of Presentation
      米国
    • Year and Date
      2007-04-15
    • Related Report
      2007 Annual Research Report
  • [Remarks] 愛知県がんセンター研究所 分子腫瘍学部 Webページ

    • URL

      http://www.pref.aichi.jp/cancer-center/400/420/421/421-03.html

    • Related Report
      2007 Annual Research Report
  • [Patent(Industrial Property Rights)] 癌の新規治療用組成物2006

    • Inventor(s)
      高橋隆, 柳澤聖, 長田啓隆
    • Industrial Property Rights Holder
      名古屋大学, 愛知県
    • Filing Date
      2006-04-27
    • Related Report
      2006 Annual Research Report

URL: 

Published: 2006-04-01   Modified: 2018-03-28  

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