Identification of micro RNAs which affected by tumor microenvironments of ovarian cancer and analysis of a potential as a therapeutic target

• Project/Area Number: 23592447
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: 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): MABUCHI Seiji 大阪大学, 医学系研究科, 助教 (00452441) ; ISOBE Aki 大阪大学, 医学系研究科, 助教 (60397619) ; HASHIMOTO Kae 大阪大学, 医学系研究科, 助教 (90612078)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 卵巣癌 / 腹膜播種 / 腹膜中皮細胞 / マイクロRNA / 骨髄由来細胞

Research Abstract

During the dissemination of ovarian cancer cells, cells are floating in the peritoneal cavity without vascular supply and exposed in hypoxic conditions. We suggest that hypoxic stimuli affect ovarian cancer cell behavior. In this study, we screened miRNAs which expression were altered under hypoxic condition. miRNA PCR arrays revealed that the expression of miR-199a-3p decreased under hypoxic conditions. In silico analyses led us to consider MET is one of the target genes of miR-199a-3p. miR-199a-3p expression was inversely correlated with c-Met expression in ovarian cancer cells. Transfection of precursor miR-199a-3p into ovarian cancer cells reduced c-Met expression followed by the inhibition of the proliferation, adhesion and invasion. In an ovarian cancer xenograft model, the enforced expression of miR-199a-3p in SKOV3 cells significantly suppressed peritoneal dissemination. Thus we suggested that miR-199a-3p is a potential target for treating ovarian cancer dissemination.

Research Products

• [Journal Article] miR-92a Inhibits Peritoneal Dissemination of Ovarian Cancer Cells by Inhibiting Integrin alpha5 Expression (2013)
  • Author(s): Ohyagi-Hara, C. Sawada, K. Kamiura, S. Tomita, Y. Isobe, A. Hashimoto, K. Kinose, Y. Mabuchi, S. Hisamatsu, T. Takahashi, T. Kumasawa, K. Nagata, S. Morishige, K. I. Lengyel, E. Kurachi, H. Kimura, T.
  • Journal Title: Am J Pathol Volume: 182 Pages: 1876-1889
• [Journal Article] Estradiol and raloxifene induce the proliferation of osteoblasts through G-protein-coupled receptor GPR30 (2013)
  • Author(s): Noda-Seino, H. Sawada, K. Hayakawa, J. Ohyagi-Hara, C. Mabuchi, S. Takahashi, K. Nishio, Y. Sakata, M. Kurachi, H. Kimura, T
  • Journal Title: J Endocrinol Invest Volume: 36 Pages: 21-27
• [Journal Article] Targeting interleukin-6 receptor inhibits preterm delivery induced by inflammation Wakabayashi (2013)
  • Author(s): A. Sawada, K. Nakayama, M. Toda, A. Kimoto, A. Mabuchi, S. Kinose, Y. Nakamura, K. Takahashi, K. Kurachi, H. Kimura, T
  • Journal Title: Mol Hum Reprod Volume: 19 Pages: 718-726
• [Journal Article] miR-92a inhibits peritoneal dissemination of ovarian cancer cells by inhibiting integrin α5 expression (2013)
  • Author(s): Ohyagi-Hara C, Sawada K, Mabuchi S, Takahashi T, Kurachi H
  • Journal Title: Am J Pathol Volume: 182(5) Issue: 5 Pages: 1876-1889
  • DOI: 10.1016/j.ajpath.2013.01.039
  • Peer Reviewed
• [Journal Article] 腹膜播種を制御するmicroRNAの同定とその作用機序の解明 (2012)
  • Author(s): 澤田健二郎
  • Journal Title: 産科と婦人科 Volume: 79 Pages: 1298-1300
  • Peer Reviewed
• [Journal Article] Foretinib (GSK1363089), an orally available multikinase inhibitor of c-Met and VEGFR-2, blocks proliferation, induces anoikis, and impairs ovarian cancer metastasis (2011)
  • Author(s): Zillhardt, M., S. M. Park, et al.
  • Journal Title: Clin Cancer Res Volume: 17 Pages: 4042-4051
  • Peer Reviewed
• [Journal Article] Ligand-independent activation of c-Met by fibronectin and alpha(5)beta(1)-integrin regulates ovarian cancer invasion and metastasis (2011)
  • Author(s): Mitra, A. K., K. Sawada, et al.
  • Journal Title: Oncogene Volume: 30 Pages: 1566-1576
  • Peer Reviewed
• [Journal Article] The activity of trabectedin as a single agent or in combination with everolimus for clear cell carcinoma of the ovary (2011)
  • Author(s): Mabuchi, S., T. Hisamatsu, et al.
  • Journal Title: Clin Cancer Res Volume: 17 Pages: 4462-73
  • Peer Reviewed
• [Presentation] Hypoxia related microRNA, miR-199a-3p, inhibits ovarian cancer progression through the suppression of c-Met expression (2013)
  • Author(s): Kinose, Y. Sawada, K. Mabuchi, S. Morishige, K. Kimura, T
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] 上皮性卵巣癌におけるmTOR complex 2 (mTORC2) の発現とその臨床的意義の検討 (2012)
  • Author(s): 久松武志、馬淵誠士、河野まひる、橋本香映、磯部晶、澤田健二郎、木村正
  • Organizer: 第64回日本産科婦人科学会学術講演会
  • Place of Presentation: 兵庫
• [Presentation] 上皮性卵巣癌におけるmTOR complex 2 (mTORC2) の発現とその臨床的意義の検討 (2012)
  • Author(s): 久松武志、馬淵誠士、河野まひる、橋本香映、磯部晶、澤田健二郎、木村正
  • Organizer: 第52回日本婦人科腫瘍学会学術講演会
  • Place of Presentation: 東京
• [Presentation] Identification of microRNA which regulates peritoneal dissemination of ovarian cancer (2011)
  • Author(s): Ohyagi, C.
  • Organizer: American Association for Cancer Research 102nd Annual Meeting 2011
  • Place of Presentation: アメリカ
• [Presentation] Analysis of functional role of interleukin-6 secreted by tumor-associated macrophages in ovarian cancer ascites (2011)
  • Author(s): Isobe, A.
  • Organizer: American Association for Cancer Research 102nd Annual Meeting 2011
  • Place of Presentation: アメリカ
• [Presentation] 子宮体癌術後の卵巣摘出に伴う骨量減少に対する予防介入臨床試験（中間報告）
  • Author(s): 澤田健二郎、馬淵誠士、久松武志、西尾幸浩、山本敏也、伊藤公彦、森重健一郎、上浦祥司、木村正
  • Organizer: 第8回 SERM学術研究会学術集会
  • Place of Presentation: 東京