Why is the treatment of peritoneal dissemination so difficult? Analyses focusing on microRNA and exosome.

• Project/Area Number: 26293360
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Osaka University
• Principal Investigator: Sawada Kenjiro 大阪大学, 医学(系)研究科(研究院), 講師 (00452392)
• Co-Investigator(Kenkyū-buntansha): 馬淵 誠士 大阪大学, 医学(系)研究科(研究院), 助教 (00452441) ; 木村 正 大阪大学, 医学(系)研究科(研究院), 教授 (90240845) ; 橋本 香映 大阪大学, 医学(系)研究科(研究院), 助教 (90612078) ; 磯部 晶 大阪大学, 医学(系)研究科(研究院), 助教 (60397619)
• Research Collaborator: Kinose Yasuto ; Nakamura Koji ; Yoshimura Akihiko
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,250,000 (Direct Cost: ¥12,500,000、Indirect Cost: ¥3,750,000); Fiscal Year 2016: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2015: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: Ovarian cancer / peritoneal dissemination / microRNA / exosome / paclitaxel / 卵巣癌 / マイクロRNA / CD44 miR-99a / バイオマーカー / 腹膜播種 / 卵巣がん / エクソソーム / パクリタキセル耐性 / 低酸素刺激

Outline of Final Research Achievements

The overcome of paclitaxel resistance is a critical issue in ovarian cancer treatment. We aimed to identify key miRNAs which regulate paclitaxel resistance and to pursue those potential as therapeutic targets. Two paclitaxel resistant ovarian cancer cell lines were established by a continuous exposure. MiRNA PCR arrays were performed and miR-194 was found to be one of down-regulated miRNAs. We found that miR-194 acts as a tumor suppressor miRNA through the sensitization to paclitaxel and can be considered as a therapeutic target for paclitaxel-resistant ovarian cancer. Further, we aimed to identify the functional roles of ovarian cancer-derived exosomes during peritoneal dissemination. Exosomes were isolated from ovarian cancer cell lines. Ovarian cancer invasion was significantly promoted in the presence of exosome-treated human peritoneal mesothelial cells (HPMCs). We proved that ovarian cancer-derived exosomes transfer CD-44 to HPMCs, which can facilitate ovarian cancer invasion.

Research Products

• [Journal Article] Exosomes Promote Ovarian Cancer Cell Invasion through Transfer of CD44 to Peritoneal Mesothelial Cells. (2017)
  • Author(s): Nakamura, K. Sawada, K. Kinose, Y. Yoshimura, A. Toda, A. Nakatsuka, E. Hashimoto, K. Mabuchi, S. Morishige, KI. Kurachi, H. Lengyel, E. Kimura, T.
  • Journal Title: Mol Cancer Res Volume: 15(1) Issue: 1 Pages: 78-92
  • DOI: 10.1158/1541-7786.mcr-16-0191
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinical relevance of circulating cell-free microRNAs in ovarian cancer. (2016)
  • Author(s): Nakamura, K. Sawada, K. Yoshimura, A. Kinose, Y. Nakatsuka, E. Kimura, T.
  • Journal Title: Mol Cancer Volume: 24;15(1) Issue: 1 Pages: 48-48
  • DOI: 10.1186/s12943-016-0536-0
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Novel IκB Kinase β Inhibitor, IMD-0560, Has Potent Therapeutic Efficacy in Ovarian Cancer Xenograft ModelMice. (2016)
  • Author(s): Sawada, I. Hashimoto, K. Sawada, K. Kinose, Y. Nakamura, K. Toda, A. Nakatsuka, E. Yoshimura, A. Mabuchi, S. Fujikawa, T. Itai, A. Kimura, T.
  • Journal Title: Int J Gynecol Cancer Volume: 26(4) Issue: 4 Pages: 610-618
  • DOI: 10.1097/igc.0000000000000668
  • Peer Reviewed / Open Access
• [Journal Article] Targeting Inhibitor of κB Kinase β Prevents Inflammation-Induced Preterm Delivery by Inhibiting IL-6 Production from Amniotic Cells. (2016)
  • Author(s): Toda, A. Sawada, K. Fujikawa, T. Wakabayashi, A. Nakamura, K. Sawada, I. Yoshimura, A. Nakatsuka, E. Kinose, Y. Hashimoto, K. Mabuchi, S. Tokuhira, A. Nakayama, M. Itai, A. Kurachi, H. Kimura, T.
  • Journal Title: Am J Pathol Volume: 186(3) Pages: 616-629
  • Peer Reviewed / Open Access
• [Journal Article] Is the exosome a potential target for cancer immunotherapy? (2016)
  • Author(s): Yoshimura, A. Sawada, K. Kimura, T.
  • Journal Title: Ann Transl Med Volume: 5(5) Issue: 5 Pages: 117-117
  • DOI: 10.21037/atm.2017.01.47
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy of raloxifene hydrochloride for the prevention of health care problems in patients who undergo surgery for endometrial cancer: a multicenter randomized clinical trial. (2015)
  • Author(s): Nakamura, K. Sawada, K. Sugiyama, M. Mabuchi, S. Hisamatsu, T. Nishio, Y. Ito, K. Kimura, T. Kamiura, S. Morishige, K.
  • Journal Title: Int J Gynecol Cancer Volume: 25 Issue: 2 Pages: 288-295
  • DOI: 10.1097/igc.0000000000000333
  • Peer Reviewed / Open Access
• [Journal Article] The hypoxia-related microRNA miR-199a-3p displays tumor suppressor functions in ovarian carcinoma (2015)
  • Author(s): Kinose, Y. Sawada, K. Nakamura, K. Sawada, I. Toda, A. Nakatsuka, E. Hashimoto, K. Mabuchi, S. Takahashi, K. Kurachi, H. Lengyel, E. Kimura, T.
  • Journal Title: Oncotarget Volume: -
  • Peer Reviewed / Open Access
• [Journal Article] Interleukin 6 receptor is an independent prognostic factor and a potential therapeutic target of ovarian cancer. (2015)
  • Author(s): Isobe A, Sawada K, Kinose Y, Ohyagi-Hara C, Nakatsuka E, Makino H, Ogura T, Mizuno T, Suzuki N, Morii E, Nakamura K, Sawada I, Toda A, Hashimoto K, Mabuchi S, Ohta T, Morishige K, Kurachi H, Kimura T.
  • Journal Title: PloS One Volume: 10 Issue: 2 Pages: e0118080-e0118080
  • DOI: 10.1371/journal.pone.0118080
  • Peer Reviewed / Open Access
• [Journal Article] IKKβ Regulates VEGF Expression and Is a Potential Therapeutic Target for Ovarian Cancer as an Anti-angiogenic Treatment (2015)
  • Author(s): Kinose, Y. Sawada, K. Makino, H. Ogura, T. Mizuno, T. Suzuki, N. Fujikawa, T. Morii, E. Nakamura, K. Sawada, I. Toda, A. Hashimoto, K. Isobe, A. Mabuchi, S. Ohta, T. Itai, A. Morishige, K. I. Kurachi, H. Kimura, T
  • Journal Title: Mol Cancer Ther Volume: 14 Issue: 4 Pages: 909-19
  • DOI: 10.1158/1535-7163.mct-14-0696
  • Peer Reviewed / Open Access
• [Presentation] 婦人科癌治療に伴う骨粗鬆症に対する介入試験 - デノスマブとリセドロネートの治療効果の比較検討 (2016)
  • Author(s): 中塚えりか 澤田健二郎 木瀬康人 吉村明彦 黒田浩正 小笹勝巳 中村幸司 馬淵誠士 木村正
  • Organizer: 第31回日本女性医学学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2016-11-05
• [Presentation] 婦人科悪性腫瘍治療後の卵巣機能喪失により生じる不定愁訴に対する漢方薬治療の可能性の検討 (2016)
  • Author(s): 吉村明彦 澤田健二郎 笹野智之 小笹勝巳 黒田浩正 中塚えりか 中村幸司 木瀬康人 木村正
  • Organizer: 第31回日本女性医学学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2016-11-05
• [Presentation] 婦人科癌治療に伴う骨粗鬆症に対するデノスマブの有用性の検討 (2016)
  • Author(s): 中塚えりか 澤田健二郎 木瀬康人 吉村明彦 黒田浩正小笹勝巳 小玉美智子 橋本香映 中村幸司 馬淵誠士 木村正
  • Organizer: 第135回近畿産婦人科学会
  • Place of Presentation: 京都
  • Year and Date: 2016-10-22
• [Presentation] Elevated level of serum miR-99a is correlated with serous epithelial ovarian cancer and can be a potential biomarker. (2016)
  • Author(s): Yoshimura, A. Sawada, K. Nakamura, K. Kinose, Y. Nakatsuka, E. Mabuchi, S. Kimura, T.
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] Analysis of PAI-1 (plasmin activator inhibitor 1) as a potential therapeutic target for ovarian cancer. (2016)
  • Author(s): Nakatsuka, E. Sawada, K. Nakamura, K. Yoshimura, A. Kinose, Y. Mabuchi, S. Itai, A. Kimura, T.
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] Elevated level of circulating microRNA-99a correlates with serous epithelial ovarian cancer and can be used as a potential biomarker. (2016)
  • Author(s): Yoshimura, A. Sawada, K. Nakamura, K. Kinose, Y. Nakatsuka, E. Mabuchi, S. Kimura, T.
  • Organizer: 第68回日本産科婦人科学会学術講演会
  • Place of Presentation: 東京
  • Year and Date: 2016-04-21
• [Presentation] PAI-1（plasmin activator inhibitor 1）as a therapeutic target for ovarian cancer. (2016)
  • Author(s): Nakatsuka, E. Sawada, K. Nakamura, K. Yoshimura, A. Makino, H. Sawada, I. Toda, A. Mabuchi, S. Morishige, K. Kimura, T.
  • Organizer: 第68回日本産科婦人科学会学術講演会
  • Place of Presentation: 東京
  • Year and Date: 2016-04-21
• [Presentation] Elevated level of circulating microRNA-99a is correlated with serous epithelial ovarian cancer and can be used as a potential biomarker. (2016)
  • Author(s): Yoshimura, A. Sawada, K. Nakamura, K. Kinose, Y. Nakatsuka, E. Mabuchi, S. Kimura, T.
  • Organizer: AACR Annual Meeting 2016
  • Place of Presentation: New Orleans, Louisiana, USA
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Presentation] Ovarian cancer cells promote cancer invasion by transferring CD44 to mesothelial cells via exosomes. (2015)
  • Author(s): Koji Nakamura, Kenjiro Sawada, Yasuto Kinose, Erika Nakatsuka, Akihiko Yoshimura, Seiji Mabuchi, Tadashi Kimura
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] 卵巣がんにおける PAI-1 (プラスミノーゲン活性化抑制因子 1)の 発現の解析及び新規阻害剤の治療応用への可能性の検討 (2015)
  • Author(s): 中塚 えりか、澤田 健二郎、中村 幸司、吉村 明彦、木瀬 康人、馬淵 誠士、木村 正
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] Ovarian cancer exosomes promote invasion by affecting mesothelial cells through the upregulation of MMP9 secretion and mesothelial cell barrier. (2015)
  • Author(s): Koji Nakamura, Kenjiro Sawada, Yasuto Kinose, Akihiko Yoshimura, Erika Nakatsuka, Seiji Mabuchi, Tadashi Kimura
  • Organizer: 第57回日本婦人科腫瘍学会学術講演会
  • Place of Presentation: 盛岡
  • Year and Date: 2015-08-07
• [Presentation] Exosome transfer from ovarian cancer cells to mesothelial cells promotes cell invasion by upregulating MMP-9 secretion and increasing clearance of mesothelial cells. (2015)
  • Author(s): Koji Nakamura, Kenjiro Sawada, Yasuto Kinose, Akihiko Yoshimura, Erika Nakatsuka, Seiji Mabuchi, Tadashi Kimura.
  • Organizer: American Association for Cancer Research Annual Meeting 2015
  • Place of Presentation: America, Pennsylvania
  • Year and Date: 2015-04-18
  • Int'l Joint Research
• [Presentation] 卵巣癌細胞由来exosome の腹膜中皮細胞への情報伝達機構の解明―癌細胞由来CD44 はexosome により中皮細胞に移行し，腹膜中皮のMMP 9 分泌促進，Ecadherin 発現抑制を誘導し腹膜播種を促進する (2015)
  • Author(s): 中村幸司 澤田健二郎 木瀬康人 吉村明彦 中塚えりか 戸田有朱香 橋本香映 馬淵誠士 木村正
  • Organizer: 第6７回日本産科婦人科学会学術講演会
  • Place of Presentation: 横浜
  • Year and Date: 2015-04-09
• [Presentation] 卵巣がんにおけるPAI 1（プラスミノーゲン活性化抑制因子1）の発現の検討とその阻害剤の抗がん治療への可能性の検討 (2015)
  • Author(s): 中塚えりか 澤田健二郎 中村幸司 吉村明彦 木瀬康人 澤田育子 戸田有朱香 馬淵誠士 木村正
  • Organizer: 第6７回日本産科婦人科学会学術講演会
  • Place of Presentation: 横浜
  • Year and Date: 2015-04-09
• [Presentation] 婦人科癌治療後により生じる骨密度低下に対するリセドロン酸ナトリウム水和物（リセドロネート）の有用性の検討 (2014)
  • Author(s): 木瀬康人. 澤田健二郎. 戸田有朱香. 笹野智之. 澤田育子. 松本有里. 坂田正博. 木村 正
  • Organizer: 第29回日本女性医学学会
  • Place of Presentation: 東京
  • Year and Date: 2014-11-01 – 2014-11-02
• [Presentation] 大阪大学における前置胎盤、前置癒着胎盤手術の治療成績と工夫 (2014)
  • Author(s): 木瀬康人. 小笹勝巳. 松崎慎哉. 金川武司. 澤田健二郎. 木村 正
  • Organizer: 第37回日本産婦人科手術学会
  • Place of Presentation: 札幌
  • Year and Date: 2014-10-11 – 2014-10-12
• [Presentation] 低酸素関連 microRNA、miR-199a-3p は c-Met の発現抑制により卵巣癌腹膜播種の進展を抑制する (2014)
  • Author(s): 木瀬康人. 澤田健二郎. 馬淵誠士. 木村 正
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 卵巣癌においてmiR-194はBMI-1を制御することでパクリタキセル耐性を減弱させる (2014)
  • Author(s): 中村幸司. 澤田健二郎. 木瀬康人. 橋本香映. 木村 正
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] The effect of raloxifene hydrochloride for the prevention of health care problems of patients who underwent surgeries for endometrial cancer: A multicenter clinical trial (2014)
  • Author(s): Nakamura, K. Sawada, K. Sugiyama, M. Mabuchi, S. Hisamatsu, T. Nishio, Y. Ito, K. Kimura, T. Kamiura, S. Morishige, K.
  • Organizer: 50th Annual Meeting of the American Society of Clinical Oncology
  • Place of Presentation: Chicago, U.S.A.
  • Year and Date: 2014-05-30 – 2014-06-03
• [Presentation] 子宮体癌術後のヘルスケアに関する多施設共同非盲検ランダム化比較試験-ラロキシフェンは骨密度を上昇させ、コレステロール値を低下させる (2014)
  • Author(s): 中村幸司. 澤田健二郎. 杉山三知代. 馬淵誠士. 久松武志. 西尾幸浩. 伊藤公彦. 森重健一郎. 木村 正. 上浦祥司
  • Organizer: 第66回日本産科婦人科学会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-18 – 2014-04-20
• [Presentation] 低酸素環境下で発現が変動する microRNA の網羅的解析を通じた卵巣癌腹膜播種抑制の分子標的治療の可能性-低酸素刺激で発現低下を示すmiR-199a-3pはc-Metの発現抑制を通じて播種進展を抑制する (2014)
  • Author(s): 木瀬康人. 澤田健二郎. 中村幸司. 牧野 弘. 水野智子. 橋本香映. 磯部 晶. 馬淵誠士. 坂田正博. 森重健一郎. 木村 正
  • Organizer: 第66回日本産科婦人科学会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-18 – 2014-04-20
• [Presentation] Hypoxia related microRNA, miR-199a-3p, inhibits ovarian cancer progression through the suppression of c-Met expression (2014)
  • Author(s): Kinose, Y. Sawada, K. Nakamura, K. Mabuchi, S. Morishige, K. Kimura, T.
  • Organizer: 105th Annual Meeting of the American Association for Cancer Research
  • Place of Presentation: San Diego, U.S.A.
  • Year and Date: 2014-04-05 – 2014-04-09
• [Presentation] Identification of microRNA which regulates paclitaxel resistance of ovarian cancer cells - a potential of miR-194 by attenuating paclitaxel resistance through the down-regulation of oncogene BMI-1 (2014)
  • Author(s): Nakamura, K. Sawada, K. Kinose, Y. Hashimoto, K. Mabuchi, S. Kimura, T.
  • Organizer: 105th Annual Meeting of the American Association for Cancer Research
  • Place of Presentation: San Diego, U.S.A.
  • Year and Date: 2014-04-05 – 2014-04-09