Molecular mechanisms for chemoresistance to Paclitaxel in ovariancancer

• Project/Area Number: 19591941
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Iwate 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: ¥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)
• Keywords: Paclitaxel / 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.

Research Products

• [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 129 Pages: 1516-16
• [Journal Article] Second-line treatment using novel chemotherapeutic and biologic agents (2009)
  • Author(s): Sugiyama T.
  • Journal Title: Gan To Kagaku Ryoho 36 Pages: 730-5
• [Journal Article] Development and significance of a fetal electrocardiogram recorded by signal-averaged high-amplification electrocardiography (2009)
  • Author(s): Hayashi R, Nakai K, Fukushima A, Itoh M, Sugiyama T.
  • Journal Title: Int Heart J 50 Pages: 161-71
  • NAID: 130000108082
• [Journal Article] Treatments of epithelial ovarian cancer by histologic subtype (2009)
  • Author(s): Sugiyama T, Kumagai S, Hatayama S.
  • Journal Title: Gan To Kagaku Ryoho 36 Pages: 187-92
• [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)
  • Peer Reviewed
• [Journal Article] Interaction between NACC1, a BTB/POZ family member, and histone deacetylase 6 is involved in microtubule acetylation in tumor cells (2009)
  • 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)
  • 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 growth (2009)
  • Author(s): Akasaka K, Maesawa C, Shibazaki M, Maeda F, Takahashi K, Akasaka T, Masuda T.
  • Journal Title: Oncogene (印刷中)
  • Peer Reviewed
• [Journal Article] Epigenetic modification is involved in aberrant expression of class III beta-tubulin, TUBB3, in ovarian cancer cells (2008)
  • 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
• [Journal Article] Emerging drugs for ovarian cancer (2008)
  • Author(s): Sugiyama T, Konishi I.
  • Journal Title: Expert Opin Emerg Drugs 13 Pages: 523-26
• [Journal Article] Classification and treatment of ovarian cancer (2008)
  • Author(s): Sugiyama T, Kou T.
  • Journal Title: Gan To Kagaku Ryoho 35 Pages: 228-32
• [Journal Article] Epigenetic modification is involved in aberrant expression of class III β-tubulin, TUBB3, in ovarian cancer cells (2008)
  • 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
  • Peer Reviewed
• [Journal Article] Ovarian cancer treatment from the standpoint of the gynecologic oncologist (2007)
  • Author(s): Sugiyama T, Yoshizaki A, Hatayama S.
  • Journal Title: Gan To Kagaku Ryoho 34 Pages: 1011-6
• [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)
• [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)
• [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)
  • 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
• [Presentation] Loss of TUBB3 induced by histone deacetylation is associated with chemosensitivity to Paclitaxel in melanoma cells (2007)
  • 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
• [Presentation] Epigenetic modification is involved in aberrant expression of TUBB3 in ovarian cancer cells (2007)
  • 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