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Molecular mechanisms for chemoresistance to Paclitaxel in ovariancancer

Research Project

Project/Area Number 19591941
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Obstetrics and gynecology
Research InstitutionIwate Medical University

Principal Investigator

SUGIYAMA Toru  Iwate Medical University, 医学部, 教授 (40162903)

Co-Investigator(Kenkyū-buntansha) MAESAWA Chihaya  岩手医科大学, 医学部, 教授 (10326647)
熊谷 晴介  岩手医科大学, 医学部, 講師 (20289474)
Co-Investigator(Renkei-kenkyūsha) KUMAGAI Seisuke  岩手医科大学, 医学部, 教授 (20289474)
Project Period (FY) 2007 – 2008
Project Status Completed (Fiscal Year 2008)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2008: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2007: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
KeywordsPaclitaxel / TUBB3 / 卵巣癌 / 悪性黒色腫 / エピジェネティックス / DNAメチル化 / ヒストンアセチル化 / 薬剤耐性 / paclitaxel / RE-1 / 予後 / REST / DNAメチル / ヒストンアセチル
Research Abstract

卵巣癌おけるPaclitaxel感受性に関するtype IIIβ-tubulin(TUBB3)の過剰発現の影響と, その転写制御機構を解析した. 転写制御に関しては, 転写因子RESTの関与とそれに纏わるエピジェネティックな制御機構, 遺伝子の構造異常について解析した. また, 卵巣癌原発巣におけるTUBB3の発現と臨床病理学的事項との相関も検討した. さらに, 卵巣癌以外の悪性腫瘍に関しても解析を行った. 卵巣癌においてTUBB3の過剰発現は, 進行度や転移などの予後不良マーカーと有意に相関した. TUBB3の過剰発現は, REST結合領域のRE-1配列近傍のメチル化状態とヒストン蛋白のアセチル化状態に依存していた. TUBB3過剰発現卵巣癌培養細胞株ではPaclitaxelに対する感受性が低下していた. REST遺伝子はいずれの細胞株でも安定的に発現しており, 構造異常も認められず, TUBB3の発現に関して直接的関与は認めなかった. REST inducible cloneによるdominant negative cloneでは, RESTはMeCP2ならびにSim3等の巨大なepigenetic regulator bodyを形成し, TUBB3の発現を細胞周期依存性に制御している可能性が示唆された. 卵巣癌におけるTUBB3の異常発現は,その発現制御因子である転写因子RESTの結合領域に生じるエピジェネティックな機構の破綻による可能性が示唆された. 悪性黒色腫では, TUBB3過剰発現株では卵巣癌と同様にPaclitaxelに対して抵抗性を持つものの, 予後は逆に良好であった. このことはTUBB3の過剰発現は腫瘍によって異なる生物学的特性を付与すると考えられた. 卵巣癌のPaclitaxelを用いた治療において, TUBB3の免疫組織学的解析は重要な情報である. さらに, Paclitaxelを主体とした化学療法施行に際して, エピジェネティックな腫瘍環境を考慮する必要があると考えられた.

Report

(3 results)
  • 2008 Annual Research Report   Final Research Report ( PDF )
  • 2007 Annual Research Report
  • Research Products

    (18 results)

All 2009 2008 2007 Other

All Journal Article (15 results) (of which Peer Reviewed: 5 results) Presentation (3 results)

  • [Journal Article] Loss of class III beta-tubulin induced by histone deacetylation is associated with chemosensitivity to paclitaxel in malignant melanoma cells2009

    • Author(s)
      Akasaka K, Maesawa C, Shibazaki M, Maeda F, Takahashi K, Akasaka T, Masuda T.
    • Journal Title

      J Invest Dermatol 129

      Pages: 1516-16

    • Related Report
      2008 Final Research Report
  • [Journal Article] Second-line treatment using novel chemotherapeutic and biologic agents2009

    • Author(s)
      Sugiyama T.
    • Journal Title

      Gan To Kagaku Ryoho 36

      Pages: 730-5

    • Related Report
      2008 Final Research Report
  • [Journal Article] Development and significance of a fetal electrocardiogram recorded by signal-averaged high-amplification electrocardiography2009

    • Author(s)
      Hayashi R, Nakai K, Fukushima A, Itoh M, Sugiyama T.
    • Journal Title

      Int Heart J 50

      Pages: 161-71

    • NAID

      130000108082

    • Related Report
      2008 Final Research Report
  • [Journal Article] Treatments of epithelial ovarian cancer by histologic subtype2009

    • Author(s)
      Sugiyama T, Kumagai S, Hatayama S.
    • Journal Title

      Gan To Kagaku Ryoho 36

      Pages: 187-92

    • Related Report
      2008 Final Research Report
  • [Journal Article] Loss of Class III beta-tubulin induced by histone deacetylation is associated with chemosensitivity to paclitaxel in malignant melanoma cells.2009

    • Author(s)
      Akasaka K, Maesawa C, Shibazaki M, Maeda F, Takahashi K, Akasaka T, Masuda T.
    • Journal Title

      J Invest Dermatol (印刷中)

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Interaction between NACC1, a BTB/POZ family member, and histone deacetylase 6 is involved in microtubule acetylation in tumor cells2009

    • Author(s)
      Tada T, Maesawa C, Oikawa H, Tatemichi Y, Shibazaki M, Kanno S, Muraoka S, Miyamoto A, Nishida J, Shimamura T, Sugiyama T, Wakabayashi G, Masuda T
    • Journal Title

      J Biol Chem (印刷中)

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cell cycle-dependent expression of class III β-tubulin by NRSF/REST in non-neuronal cells and its involvement in cell growth2009

    • Author(s)
      Akasaka K, Maesawa C, Shibazaki M, Maeda F, Takahashi K, Akasaka T, Masuda T.
    • Journal Title

      Oncogene (印刷中)

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Epigenetic modification is involved in aberrant expression of class III beta-tubulin, TUBB3, in ovarian cancer cells2008

    • Author(s)
      Izutsu N, Maesawa C, Shibazaki M, Oikawa H, Shoji T, Sugiyama T, Masuda T
    • Journal Title

      Int J Oncol 32

      Pages: 1227-35

    • Related Report
      2008 Final Research Report
  • [Journal Article] Emerging drugs for ovarian cancer2008

    • Author(s)
      Sugiyama T, Konishi I.
    • Journal Title

      Expert Opin Emerg Drugs 13

      Pages: 523-26

    • Related Report
      2008 Final Research Report
  • [Journal Article] Classification and treatment of ovarian cancer2008

    • Author(s)
      Sugiyama T, Kou T.
    • Journal Title

      Gan To Kagaku Ryoho 35

      Pages: 228-32

    • Related Report
      2008 Final Research Report
  • [Journal Article] Epigenetic modification is involved in aberrant expression of class III β-tubulin, TUBB3, in ovarian cancer cells2008

    • Author(s)
      Izutsu N, Maesawa C, Shibazaki M, Oikawa H, Shoji T, Sugiyama T, Masuda T
    • Journal Title

      Int J Oncol 32

      Pages: 1227-1235

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ovarian cancer treatment from the standpoint of the gynecologic oncologist2007

    • Author(s)
      Sugiyama T, Yoshizaki A, Hatayama S.
    • Journal Title

      Gan To Kagaku Ryoho 34

      Pages: 1011-6

    • Related Report
      2008 Final Research Report
  • [Journal Article] Wakabayashi G, Masuda T. Interaction between NACC1, a BTB/POZ family member, and histone deacetylase 6 is involved in microtubule acetylation in tumor cells

    • Author(s)
      Tada T, Maesawa C, Oikawa H, Tatemichi Y, Shibazaki M, Kanno S, Muraoka S, Miyamoto A, Nishida J, Shimamura T, Sugiyama T
    • Journal Title

      J Biol Chem (in press)

    • Related Report
      2008 Final Research Report
  • [Journal Article] Cell cycle-dependent regulation of class III β-tubulin by NRSF/REST in non-neuronal cells and its involvement in cell growth

    • Author(s)
      Shibazaki M, Akasaka K, Maesawa C, Mori N, Masuda T.
    • Journal Title

      Oncogen, (in press)

    • Related Report
      2008 Final Research Report
  • [Journal Article] Epigenetic modification is involved in aberrant expression of classIII β-tubulin,TUBB3,in ovarian cancer cells

    • Author(s)
      Izutsu N, Maesawa C, Shibazaki M, Oikawa H, Shoji T, Sugiyama T, Masuda T
    • Journal Title

      Int J Oncol (In press)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Presentation] 卵巣癌におけるβIII-tubulin過剰発現に関わるエピジェネティックな制御機構2008

    • Author(s)
      井筒直子, 阿保亜紀子, 前沢千早, 増田友之
    • Organizer
      第97回日本病理学会総会
    • Place of Presentation
      金沢
    • Related Report
      2008 Final Research Report
  • [Presentation] Loss of TUBB3 induced by histone deacetylation is associated with chemosensitivity to Paclitaxel in melanoma cells2007

    • Author(s)
      Akasaka K, Maesawa C, Sakurai E, Masuda T.
    • Organizer
      第67回日本癌学会総会
    • Place of Presentation
      名古屋
    • Related Report
      2008 Final Research Report
  • [Presentation] Epigenetic modification is involved in aberrant expression of TUBB3 in ovarian cancer cells2007

    • Author(s)
      Izutsu N, Maesawa C, Sugiyama T, Masuda T.
    • Organizer
      第67回日本癌学会総会
    • Place of Presentation
      名古屋
    • Related Report
      2008 Final Research Report

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Published: 2007-04-01   Modified: 2016-04-21  

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