molecular mechanism of chemoresistance in ovarian cancer cells

• Project/Area Number: 22591844
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Hokkaido University
• Principal Investigator: WATARI Hidemichi 北海道大学, 北海道大学病院, 講師 (10344508)
• Co-Investigator(Kenkyū-buntansha): SAKURAGI Noriaki 北海道大学, 大学院・医学研究科, 教授 (70153963)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2010: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 婦人科腫瘍学 / 卵巣癌 / 抗がん剤耐性 / microRNA / 抗ガン剤耐性 / MET / MET阻害剤 / micro RNA / アポトーシス / 抗癌剤耐性 / micfroRNA / clusterin

Research Abstract

We aimed to investigate the molecular mechanism of chemoresistance and to find molecular targets to overcome chemoresistance in ovarian cancer cells. We reported that clusterin, an antiapoptotic molecule, is upregulated in paclitaxel-resistant ovarian cancer cells compared to parental cells, introduction of si-RNA or antisenseoligonucleotide against clusterin sensitized paclitaxel-resistant ovarian cancer cells to paclitaxel,clusterin immunoreactivity in ovarian cancer tissues inversely correlates with response to chemotherapy and is a prognosticator for early-stage ovarian cancer. We also reported that microRNA-31 (miR-31) is down-regulated in paclitaxel-resistant ovarian cancer cells compared to parental cells, introduction of miR-31 senstized paclitaxel-rsistant ovarian cancer cells to paclitaxel, MET, a receptor tyrosine kinase, is a direct target molecule and MET can be involved in the resistant mechanisim against paclitaxel and MET inhibitor can sensitize paclitaxel-resistant ovarian cancer cells to paclitaxel.

Research Products

• [Journal Article] Downregulation of miR-31 induces taxane resistance in ovarian cancer cells through increase of receptor tyrosine kinase MET (2013)
  • Author(s): Mitamura T, Watari H, Wang L, Kanno H, Hassan MK, Miyazaki M, Katoh Y, Kimura T, Tanino M, Nishihara H, Tanaka S, Sakuragi N
  • Journal Title: Oncogenesis Volume: 2
  • Peer Reviewed
• [Journal Article] Downregulation of miRNA-31 induces taxane resistance in ovarian cancer cells through increase of receptor tyrosine kinase MET (2013)
  • Author(s): Takashi Mitamura
  • Journal Title: Oncogenesis Volume: 2 Issue: 3 Pages: e40-e40
  • DOI: 10.1038/oncsis.2013.3
  • Peer Reviewed
• [Journal Article] Clusterin is a potential molecular predictor for ovarian cancer patients'survival: targeting clusterin improves reponse to paclitaxel (2011)
  • Author(s): Hassan MK, Watari H, Han Y, Mitamura T, Hosaka M, Wang L, Tanaka S, Sakuragi N
  • Journal Title: J Exp Clin Cancer Res Volume: 30 Pages: 113-113
  • Peer Reviewed
• [Journal Article] Intracellular clusterin negatively regulates ovarian chemoresistance: compromised expression sensitizes ovarian cancer cells to paclitaxel (2011)
  • Author(s): Hassan MK, Watari H, Christenson LK, Bettuzzi S, Sakuragi N
  • Journal Title: Tumor Biol Volume: 32 Pages: 1031-47
  • Peer Reviewed
• [Journal Article] Clusterin is a potentiaa molecular predictor for ovarian cancer patients' survival : Targeting clusterin improves response to paclitaxel (2011)
  • Author(s): Hassan MK, Watari H, Han Y, Mitamura T, Hosaka M, Wang L, Tanaka s, Sakuragi N
  • Journal Title: Journal of Experimmental & Clinical Cancer Research Volume: 30 Issue: 1 Pages: 113-113
  • DOI: 10.1186/1756-9966-30-113
  • Peer Reviewed
• [Journal Article] Multivariate survival analysis of the patients with recurrent endometria 1 cancer (2011)
  • Author(s): Odagiri T, Watari H, Hosaka M, Mitamura T, Konno Y, Kato T, Kobayashi N, Sudo S, Takeda M, Kaneuchi M, Sakuraei N.
  • Journal Title: Journal of Gynecologic Oncology Volume: 22 Pages: 3-8
  • Peer Reviewed
• [Journal Article] Clusterin expression inversely correlates with chemosensitivity and predicts poor survival in patients with locally advanced cervical cancer treated with cisplatin-based neoadjuvant chemotherapy and radical hysterectomy (2010)
  • Author(s): Watari H, Kanuma T, Ohta Y, Hassan MK, Mitamura T, Hosaka M, Minegishi T, Sakuragi N.
  • Journal Title: Pathology and Oncology Research Volume: 16 Pages: 345-352
  • Peer Reviewed
• [Presentation] Downregulation of miR-31 induces taxane resistance in ovarian cancer cells through increase of receptor tyrosine kinase MET (2013)
  • Author(s): Hidemichi Watari, Takashi Mitamura, Noriaki Sakuragi
  • Organizer: 2013 SGI Annual Scientific Meeting
  • Place of Presentation: Hilton Orland Bonnet Creek(USA)
• [Presentation] Downregulation of miR-31 induces taxane resistance in ovarian cancer cells through increase of receptor tyrosine kinase MET (2013)
  • Author(s): Hidemichi Watari
  • Organizer: 2013 SGI Annual Scientific Meeting
  • Place of Presentation: Hilton Orland Bonnet Creek (USA)
• [Presentation] micrRNA-31の発現低下は、レセプターチロシンキナーゼMETの発現を介して卵巣癌のタキサン耐性を引きおこす (2012)
  • Author(s): 三田村卓、渡利英道、遠藤大介、田中理恵子、中谷真紀子、小田切哲二、金野陽輔、加藤達矢、保坂昌芳、小林範子、首藤聡子、武田真人、金内優典、工藤正尊、水上尚典、櫻木範明
  • Organizer: 日本産科婦人科学会
  • Place of Presentation: 神戸国際会議場(兵庫県)(発表確定)
  • Year and Date: 2012-04-14
• [Presentation] 卵巣漿液性腺癌においてmicroRNA-31の発現低下によりpaclitaxel感受性が変化する (2012)
  • Author(s): 三田村卓、渡利英道、櫻木範明
  • Organizer: 第52回日本婦人科腫瘍学会学術講演会
  • Place of Presentation: 高輪プリンスホテル(東京)
• [Presentation] microRNA-31の発現低下はレセプターチロシンキナーゼMETの発現を介して卵巣癌のタキサン耐性を引き起こす (2012)
  • Author(s): 三田村卓、渡利英道、櫻木範明
  • Organizer: 第64回日本産科婦人科学会学術講演会
  • Place of Presentation: 神戸国際会議場(神戸)
• [Presentation] microRNA-31の発現低下はレセプターチロシンキナーゼMEtの発現を介して卵巣癌のタキサン耐性を引き起こす (2012)
  • Author(s): 三田村 卓
  • Organizer: 第64回日本産科婦人科学会
  • Place of Presentation: 神戸国際会議場（神戸市）
• [Presentation] 卵巣漿液性腺癌においてmicroRNA-31の発現低下によりpaclitaxel感受性が変化する (2012)
  • Author(s): 三田村 卓
  • Organizer: 第52回日本婦人科腫瘍学会
  • Place of Presentation: 高輪プリンスホテル（東京都）
• [Presentation] microRNA expression profiling in a paclitaxel-resistant ovarian cancer cell line; miR-31 is involved in the acquired resistance to paclitaxel (2010)
  • Author(s): Watari H, Hassan MK, Mitamura T, Sakuragi N.
  • Organizer: 13^<th> Biennial Meeting of IGCS
  • Place of Presentation: プラハ、チェコ共和国
  • Year and Date: 2010-10-26