Clarification of microenvironment-stress induced metastasis and its targeting approach in ovarian cancer

• Project/Area Number: 24390380
• 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: Nagoya University
• Principal Investigator: KAJIYAMA HIROAKI 名古屋大学, 医学(系)研究科(研究院), 准教授 (00345886)
• Co-Investigator(Kenkyū-buntansha): SHIBATA Kiyosumi 名古屋大学, 大学医学系研究科, 准教授 (90335026)
• Co-Investigator(Renkei-kenkyūsha): SENGA Takeshi 名古屋大学, 大学医学系研究科, 准教授 (80419431)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000); Fiscal Year 2014: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2013: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2012: ¥10,010,000 (Direct Cost: ¥7,700,000、Indirect Cost: ¥2,310,000)
• Keywords: 卵巣癌 / 腹膜播種 / 上皮間葉転換 / 薬剤耐性 / 腹膜中皮細胞 / 転写因子 / 微小環境 / 上皮間葉転換(EMT) / 転移浸潤 / 腹膜中皮 / ストレス誘導転移

Outline of Final Research Achievements

This study aimed to generate new therapeutic approach targeting EMT-induced transcriptional factors specific for ovarian cancer (OC). We show that two homeoproteins, HOXB13 and ALX4, are associated with EMT and invasion of OC cells. HOXB13 and ALX4 formed a complex in cells and exogenous expression of either protein promoted EMT and invasion. Knockdown of HOXB13 or ALX4 suppressed SLUG expression and exogenous expression of either protein promoted SLUG expression. Finally we showed that SLUG expression was essential for the HOXB13- or ALX4-mediated EMT and invasion. Our results show that HOXB13/SLUG and ALX4/SLUG axes are novel pathways that promote EMT and invasion of OC cells. Furthermore, in the current study, we showed the role of ZEB1, a member of zinc-finger E-box binding homeobox (ZFH) family, in metastasis and chronic paclitaxel resistance in OC.

Research Products

• [Journal Article] HOXB13 and ALX4 induce SLUG expression for the promotion of EMT and cell invasion in ovarian cancer cells (2015)
  • Author(s): 1.Yuan H, Kajiyama H, Ito S, Chen D, Shibata K, Hamaguchi M, Kikkawa F, Senga T.
  • Journal Title: Oncotarget Volume: in press
  • Peer Reviewed
• [Journal Article] GPC3 expression in mouse ovarian cancer induces GPC-specific T cell-mediated immune response through M1 macrophages and suppresses tumor growth. (2014)
  • Author(s): Luo C, Shibata K, Suzuki S, Kajiyama H, Senga T, Koya Y, Daimon M, Yamashita M, Kikkawa F.
  • Journal Title: Oncol Rep. Volume: 32 Issue: 3 Pages: 913-21
  • DOI: 10.3892/or.2014.3300
  • Peer Reviewed / Open Access
• [Journal Article] Expression of the miR200 Family of microRNAs in Mesothelial Cells Suppresses the Dissemination of Ovarian Cancer Cells. (2014)
  • Author(s): Sugiyama K, Kajiyama H, Shibata K, Yuan H, Kikkawa F, Senga T.
  • Journal Title: Mol Cancer Ther. Volume: 13 Issue: 8 Pages: 2081-91
  • DOI: 10.1158/1535-7163.mct-14-0135
  • Peer Reviewed
• [Journal Article] PLAGL2 regulates actin cytoskeletal architecture and cell migration. (2014)
  • Author(s): Sekiya R, Maeda M, Yuan H, Asano E, Hyodo T, Hasegawa H, Ito S, Shibata K, Hamaguchi M, Kikkawa F, Kajiyama H, Senga T.
  • Journal Title: Carcinogenesis Volume: 35 Issue: 9 Pages: 1993-2001
  • DOI: 10.1093/carcin/bgu081
  • Peer Reviewed
• [Journal Article] PLAGL2 regulates actin cytoskeletalarchitecture and cell migration. (2014)
  • Author(s): Sekiya R, Maeda M, Yuan H, Asano E, Hyodo T, Hasegawa H, Ito S, Shibata K,Hamaguchi M, Kikkawa F, Kajiyama H, Senga T
  • Journal Title: Carcinogenesis Volume: in press
  • Peer Reviewed
• [Journal Article] Suppression of REV7 enhances cisplatin sensitivity in ovarian clear cell carcinoma cells. (2014)
  • Author(s): Niimi K, Murakumo Y, Watanabe N, Kato T, Mii S, Enomoto A, Asai M, Asai N, Yamamoto E, Kajiyama H, Shibata K, Kikkawa F, Takahashi M.
  • Journal Title: Cancer Sci. Volume: in press
  • Peer Reviewed
• [Journal Article] Recurrence-predicting prognostic factors for patients with early-stage epithelial ovarian cancer undergoing fertility-sparing surgery: a multi-institutional study. (2014)
  • Author(s): Kajiyama H, Mizuno M, Shibata K, Yamamoto E, Kawai M, Nagasaka T, Kikkawa F.
  • Journal Title: Eur J Obstet Gynecol Reprod Biol. Volume: 175 Pages: 97-102
  • DOI: 10.1016/j.ejogrb.2014.01.014
  • Peer Reviewed
• [Journal Article] Survival benefit of taxane plus platinum in recurrent ovarian cancer with non-clear cell, non-mucinous histology. (2014)
  • Author(s): Kajiyama H, Shibata K, Mizuno M, Umezu T, Suzuki S, Sekiya R, Niimi K, Mitsui H, Yamamoto E, Kawai M, Nagasaka T, Kikkawa F.
  • Journal Title: J Gynecol Oncol. Volume: 25 Issue: 1 Pages: 43-50
  • DOI: 10.3802/jgo.2014.25.1.43
  • Peer Reviewed
• [Journal Article] Expression of chromobox homolog 7 (CBX7) is associated with poor prognosis in ovarian clear cell adenocarcinoma via TRAIL-induced apoptotic pathway regulation. (2014)
  • Author(s): Shinjo K, Yamashita Y, Yamamoto E, Akatsuka S, Uno N, Kamiya A, Niimi K, Sakaguchi Y, Nagasaka T, Takahashi T, Shibata K, Kajiyama H, Kikkawa F, Toyokuni S.
  • Journal Title: Int J Cancer Volume: in press
  • Peer Reviewed
• [Journal Article] ALX1 induces snail expression to promote epithelial-to-mesenchymal transition and invasion of ovarian cancer cells. (2013)
  • Author(s): Yuan H, Kajiyama H, Ito S, Yoshikawa N, Hyodo, Shibata K,Hamaguch M, Kikkawa F, Senga T.
  • Journal Title: Cancer Res Volume: 73(5) Issue: 5 Pages: 1581-1590
  • DOI: 10.1158/0008-5472.can-12-2377
  • Peer Reviewed
• [Journal Article] Effect of Indirect Nonequilibrium Atmospheric Pressure Plasma on Anti-Proliferative Activity against Chronic Chemo-Resistant Ovarian Cancer Cells In Vitro and In Vivo (2013)
  • Author(s): Fumi Utsumi, Hiroaki Kajiyama, Kae Nakamura, Hiromasa Tanaka, Masaaki Mizuno, Kenji Ishikawa, Hiroki Kondo, Hiroyuki Kano, Masaru Hori, and Fumitaka Kikkawa
  • Journal Title: PLoS ONE Volume: 8 Issue: 12 Pages: e81576-e81576
  • DOI: 10.1371/journal.pone.0081576
  • Peer Reviewed
• [Journal Article] Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer. (2013)
  • Author(s): Shen H, Fridley BL, Kajiyama H, et al
  • Journal Title: Nat Commun Volume: (in press) Issue: 1
  • DOI: 10.1038/ncomms2629
  • Peer Reviewed
• [Journal Article] Extremely poor postrecurrence oncological outcome for patients with recurrent mucinous ovarian cancer. (2013)
  • Author(s): Kajiyama H, et al
  • Journal Title: Int J Clin Oncol Volume: (in press)
  • Peer Reviewed
• [Presentation] PLAGL2 regulates cell migration and actin cytoskeleton organization. (2014)
  • Author(s): 関谷龍一郎、三井寛子、鈴木史朗、水野美香、柴田清住、梶山広明、千賀威、吉川史隆
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜市 パシフィコ横浜
  • Year and Date: 2014-10-27
• [Presentation] 薬剤耐性卵巣癌におけるEMT転写因子ZEB1および誘導因子TGF-βの関与 (2014)
  • Author(s): 坂田 純、梶山広明、関谷龍一郎、三井寛子、鈴木史朗、梅津朋和、水野美香、柴田清住、吉川史隆
  • Organizer: 第56回日本婦人科腫瘍学会学術講演会
  • Place of Presentation: 栃木県宇都宮市 栃木県総合文化センター
  • Year and Date: 2014-07-17
• [Presentation] Future Perspective of Strategic Plasma Therapy for Refractory Epithelial Ovarian Cancer (2014)
  • Author(s): Hiroaki Kajiyama, Fumi Utsumi, Kae Nakamura, Hiromasa Tanaka , Masaru Hori , Fumitaka Kikkawa
  • Organizer: The 1st International Workshop on Plasma for Cancer Treatment
  • Place of Presentation: Washington DC, USA
  • Invited
• [Presentation] PLAGL2 regulates actin stress fiber formation and cell migration (2013)
  • Author(s): Ryuichiro S, Senga T, Kajiyama H
  • Organizer: 9th Joint Conference of the American Association for Cancer Research and the Japanese Cancer Association "Breakthrough in Basic and Translational Cancer Research"
  • Place of Presentation: Hawaii, USA
  • Year and Date: 2013-02-23
• [Presentation] 薬剤耐性獲得卵巣癌細胞におけるEMT誘導性とそのメカニズム (2013)
  • Author(s): 梶山広明
  • Organizer: 第54回日本婦人科腫瘍学会学術講演会
  • Place of Presentation: 東京 港区 ホテル グランパシフィック LE DAIBA
• [Presentation] 脈管侵襲陽性例における上皮間葉転換誘導転写因子Twistの発現意義 ～子宮頸癌症例の生存分析から～ (2013)
  • Author(s): 梶山広明
  • Organizer: 第54回日本婦人科腫瘍学会学術講演会
  • Place of Presentation: 東京 港区 ホテル グランパシフィック LE DAIBA
• [Presentation] Perspective of strategic plasma therapy for prognostic improvement of patients with ovarian cancer (2013)
  • Author(s): Hiroaki Kajiyama, Fumi Utsumi, Kae Nakamura, Hiromasa Tanaka , Masaru Hori , Fumitaka Kikkawa
  • Organizer: 2013 JSAP-MRS Joint Symposia
  • Place of Presentation: Kyoto, Doshisya University
  • Invited
• [Presentation] Perspective of fertility-sparing surgery in patients with early-stage epithelial ovarian cancer (2013)
  • Author(s): Hiroaki Kajiyama
  • Organizer: Annual Symposium of KSGO and KGOG
  • Place of Presentation: Seoul, Korea
  • Invited
• [Book] EBM婦人科疾患の治療 2013-2014 (2013)
  • Author(s): 梶山広明
  • Total Pages: 522
  • Publisher: 南江堂
• [Book] 産科婦人科疾患最新治療 2013-2015 (2013)
  • Author(s): 梶山広明
  • Total Pages: 308
  • Publisher: 中外医学社
• [Book] がん・生殖医療 妊孕性温存の診療 (2013)
  • Author(s): 梶山広明
  • Total Pages: 312
  • Publisher: 医歯薬出版株式会社
• [Remarks] 名古屋大学産婦人科
  • URL: http://www.med.nagoya-u.ac.jp/obgy/
• [Remarks] 名古屋大学産婦人科
  • URL: http://www.med.nagoya-u.ac.jp/obgy/