抗老化を目的としたヒト卵巣における新規酸化ストレス経路の解明

2016 Fiscal Year Research-status Report

• Project/Area Number: 15K10704
• Research Institution: The University of Tokyo
• Principal Investigator: 平池 修 東京大学, 医学部附属病院, 准教授 (20529060)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 酸化ストレス / 卵巣 / 顆粒膜細胞 / Nrf2

Outline of Annual Research Achievements

本研究は、転写因子Nrf2およびその調節因子Keap1が、酸化ストレス経路を介してヒト卵巣顆粒膜細胞のステロイド分泌の制御および増殖をどのように調節しているかを明らかにするものである。ヒト卵巣顆粒膜細胞の初代培養系を用いて、ヒト卵巣顆粒膜細胞でのNrf2およびKeap1による酸化ストレス制御機構を解明している。
Nrf2およびKeap1が卵巣顆粒膜細胞に存在していることを免疫組織化学法にて明らかにし、ヒト卵巣顆粒膜細胞の初代培養系においてNrf2発現が酸化ストレスにより上昇することから、Nrf2が生理的に機能することを明らかにした。またNrf2をsiRNA法によるノックダウンした場合の細胞のステロイド合成経路に関しては、明らかな影響を認めることは出来なかったものの、酸化ストレス応答因子Catalase、SOD1、およびDNA修復に関与するOGG1の発現がNrf2発現と正に相関することから、Nrf2の機能が酸化ストレス防御的に機能していることを明らかにした。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

予定されていたin vitroにおける検討は順調に進んでおり、現在マウスモデルの実験へと移行を検討している。

Strategy for Future Research Activity

マウスモデルにおいて、Nrf2活性化薬であるBG12（Tecfidera)の卵巣に対する薬効を検討することと、Nrf2ノックアウトマウスにおけるBG12の役割についても検討を進める予定である。

Causes of Carryover

細胞の調子が悪いことが多く、アッセイの条件でやり直しをすることが頻回にあったため、基礎的な条件検討のみにある程度時間を費やされた。

Expenditure Plan for Carryover Budget

平成29年度においてはマウスを用いた実験系が見込まれており、またBG12により遺伝子発現が変化するものを、Chip-seqまたはRNA-seqなどで検討することも予定しているため、相当な支出を要するものと判断している。

Research Products

• [Journal Article] A Potential Role for Endoplasmic Reticulum Stress in Progesterone Deficiency in Obese Women (2017)
  • Author(s): Takahashi N, Harada M, Hirota Y, Zhao L, Azhary JM, Yoshino O, Izumi G, Hirata T, Koga K, Wada-Hiraike O, Fujii T, Osuga Y.
  • Journal Title: Endocrinology Volume: 158 Pages: 84-97
  • DOI: 10.1210/en.2016-1511.
  • Peer Reviewed
• [Journal Article] Drospirenone reduces inflammatory cytokines, vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) expression in human endometriotic stromal cells. (2017)
  • Author(s): Makabe T, Koga K, Miyashita M, Takeuchi A, Sue F, Taguchi A, Urata Y, Izumi G, Takamura M, Harada M, Hirata T, Hirota Y, Wada-Hiraike O, Fujii T, Osuga Y.
  • Journal Title: J Reprod Immunol Volume: 119 Pages: 44-48
  • DOI: 10.1016/j.jri.2016.12.002.
  • Peer Reviewed
• [Journal Article] Low uptake of fluorodeoxyglucose in positron emission tomography/computed tomography in ovarian clear cell carcinoma may reflect glutaminolysis of its cancer stem cell-like properties. (2017)
  • Author(s): Sato M, Kawana K, Adachi K, Fujimoto A, Taguchi A, Fujikawa T, Yoshida M, Nakamura H, Nishida H, Inoue T, Ogishima J, Eguchi S, Yamashita A, Tomio K, Arimoto T, Wada-Hiraike O, Oda K, Nagamatsu T, Osuga Y, Fujii T.
  • Journal Title: Oncol Rep Volume: 37 Pages: 1883-1888
  • DOI: 10.3892/or.2017.5398.
  • Peer Reviewed
• [Journal Article] Preoperative assessment of factors associated with difficulty in performing total laparoscopic hysterectomy. (2017)
  • Author(s): Saito A, Hirata T, Koga K, Takamura M, Fukuda S, Neriishi K, Pastorfide G, Harada M, Hirota Y, Wada-Hiraike O, Fujii T, Osuga Y.
  • Journal Title: J Obstet Gynaecol Res Volume: 43 Pages: 320-329
  • DOI: 10.1111/jog.13198.
  • Peer Reviewed
• [Journal Article] Vaginal Stenosis After Gonadotropin-Releasing Hormone Agonist Therapy During Treatment for Acute Lymphoblastic Leukemia. (2016)
  • Author(s): Sato M, Harada M, Oishi H, Wada-Hiraike O, Hirata T, Nagasaka K, Koga K, Fujii T, Osuga Y.
  • Journal Title: J Low Genit Tract Dis. Volume: 20 Pages: 11-13
  • DOI: 10.1097/LGT.0000000000000175.
  • Peer Reviewed
• [Journal Article] Resveratrol Enhances Apoptosis in Endometriotic Stromal Cells. (2016)
  • Author(s): Taguchi A, Koga K, Kawana K, Makabe T, Sue F, Miyashita M, Yoshida M, Urata Y, Izumi G, Tkamura M, Harada M, Hirata T, Hirota Y, Wada-Hiraike O, Fujii T, Osuga Y.
  • Journal Title: Am J Reprod Immunol Volume: 75 Pages: 486-492
  • DOI: 10.1111/aji.12489
  • Peer Reviewed
• [Journal Article] Vaginal cancer possibly caused by pessary and immunocompromised condition: Multiple risk factors may influence vaginal cancer development. (2016)
  • Author(s): Akino N, Wada-Hiraike O, Matsumoto Y, Arimoto T, Oda K, Kawana K, Osuga Y, Fujii T.
  • Journal Title: J Obstet Gynaecol Res. Volume: 42 Pages: 748-751.
  • DOI: 10.1111/jog.12958.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Systemic delivery of siRNA by actively targeted polyion complex micelles for silencing the E6 and E7 human papillomavirus oncogenes. (2016)
  • Author(s): Nishida H, Matsumoto Y, Kawana K, Christie RJ, Naito M, Kim BS, Toh K, Min HS, Yi Y, Matsumoto Y, Kim HJ, Miyata K, Taguchi A, Tomio K, Yamashita A, Inoue T, Nakamura H, Fujimoto A, Sato M, Yoshida M, Adachi K, Arimoto T, Wada-Hiraike O, Oda K, Nagamatsu T, Nishiyama N, Kataoka K, Osuga Y, Fujii T.
  • Journal Title: J Control Release Volume: 231 Pages: 29-37
  • DOI: 10.1016/j.jconrel.2016.03.016.
  • Peer Reviewed
• [Journal Article] A potential role of endoplasmic reticulum stress in development of ovarian hyperstimulation syndrome. (2016)
  • Author(s): Takahashi N, Harada M, Hirota Y, Zhao L, Yoshino O, Urata Y, Izumi G, Takamura M, Hirata T, Koga K, Wada-Hiraike O, Fujii T, Osuga Y.
  • Journal Title: Mol Cell Endocrinol. Volume: 428 Pages: 161-169
  • DOI: 10.1016/j.mce.2016.03.032
  • Peer Reviewed
• [Journal Article] Effects of 1,25-Dihydroxy Vitamin D3 on Endometriosis. (2016)
  • Author(s): Miyashita M, Koga K, Izumi G, Sue F, Makabe T, Taguchi A, Nagai M, Urata Y, Takamura M, Harada M, Hirata T, Hirota Y, Wada-Hiraike O, Fujii T, Osuga Y.
  • Journal Title: J Clin Endocrinol Metab. Volume: 101 Pages: 2371-2379
  • DOI: 10.1210/jc.2016-1515
  • Peer Reviewed
• [Journal Article] Significance of survivin as a prognostic factor and a therapeutic target in endometrial cancer. (2016)
  • Author(s): Chuwa AH, Sone K, Oda K, Ikeda Y, Fukuda T, Wada-Hiraike O, Inaba K, Makii C, Takeuchi M, Oki S, Miyasaka A, Kashiyama T, Arimoto T, Kuramoto H, Kawana K, Yano T, Osuga Y, Fujii T.
  • Journal Title: Gynecol Oncol Volume: 141 Pages: 564-569
  • DOI: 10.1016/j.ygyno.2016.04.003
• [Journal Article] Characterization of TP53 and PI3K signaling pathways as molecular targets in gynecologic malignancies. (2016)
  • Author(s): Oda K, Ikeda Y, Kashiyama T, Miyasaka A, Inaba K, Fukuda T, Asada K, Sone K, Wada-Hiraike O, Kawana K, Osuga Y, Fujii T.
  • Journal Title: J Obstet Gynaecol Res Volume: 42 Pages: 757-762
  • DOI: 10.1111/jog.13018
  • Peer Reviewed
• [Journal Article] Synergistic antitumor effects of combination PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging. (2016)
  • Author(s): Inaba K, Oda K, Aoki K, Sone K, Ikeda Y, Miyasaka A, Kashiyama T, Fukuda T, Makii C, Arimoto T, Wada-Hiraike O, Kawana K, Yano T, Osuga Y, Fujii T.
  • Journal Title: Oncotarget Volume: 7 Pages: 29577-29791
  • DOI: 10.18632/oncotarget.8807.
  • Peer Reviewed
• [Journal Article] Spheroid cancer stem cells display reprogrammed metabolism and obtain energy by actively running the tricarboxylic acid (TCA) cycle. (2016)
  • Author(s): Sato M, Kawana K, Adachi K, Fujimoto A, Yoshida M, Nakamura H, Nishida H, Inoue T, Taguchi A, Takahashi J, Eguchi S, Yamashita A, Tomio K, Wada-Hiraike O, Oda K, Nagamatsu T, Osuga Y, Fujii T.
  • Journal Title: Oncotarget Volume: 7 Pages: 33297-33305
  • DOI: 10.18632/oncotarget.8947.
  • Peer Reviewed
• [Journal Article] Inhibition of endoplasmic reticulum (ER) stress sensors sensitizes cancer stem-like cells to ER stress-mediated apoptosis. (2016)
  • Author(s): Fujimoto A, Kawana K, Taguchi A, Adachi K, Sato M, Nakamura H, Ogishima J, Yoshida M, Inoue T, Nishida H, Tomio K, Yamashita A, Matsumoto Y, Arimoto T, Wada-Hiraike O, Oda K, Nagamatsu T, Osuga Y, Fujii T.
  • Journal Title: Oncotarget Volume: 7 Pages: 51854-51864
  • DOI: 10.18632/oncotarget.10126.
  • Peer Reviewed
• [Journal Article] Neutrophil depletion reduces endometriotic lesion formation in mice. (2016)
  • Author(s): Takamura M, Koga K, Izumi G, Urata Y, Nagai M, Hasegawa A, Harada M, Hirata T, Hirota Y, Wada-Hiraike O, Fujii T, Osuga Y.
  • Journal Title: Am J Reprod Immunol Volume: 76 Pages: 193-198
  • DOI: 10.1111/aji.12540.
  • Peer Reviewed
• [Journal Article] Modification of the Tumor Microenvironment in KRAS or c-MYC-Induced Ovarian Cancer-Associated Peritonitis. (2016)
  • Author(s): Yoshida M, Taguchi A, Kawana K, Adachi K, Kawata A, Ogishima J, Nakamura H, Fujimoto A, Sato M, Inoue T, Nishida H, Furuya H, Tomio K, Arimoto T, Koga K, Wada-Hiraike O, Oda K, Nagamatsu T, Kiyono T, Osuga Y, Fujii T.
  • Journal Title: PLoS One Volume: 11 Pages: e0160330
  • DOI: 10.1371/journal.pone.0160330
  • Peer Reviewed
• [Journal Article] Cancer-associated fibroblast suppresses killing activity of natural killer cells through downregulation of poliovirus receptor (PVR/CD155), a ligand of activating NK receptor. (2016)
  • Author(s): Inoue T, Adachi K, Kawana K, Taguchi A, Nagamatsu T, Fujimoto A, Tomio K, Yamashita A, Eguchi S, Nishida H, Nakamura H, Sato M, Yoshida M, Arimoto T, Wada-Hiraike O, Oda K, Osuga Y, Fujii T.
  • Journal Title: Int J Oncol Volume: 49 Pages: 1297-1304
  • DOI: 10.3892/ijo.2016.3631.
  • Peer Reviewed
• [Journal Article] Development of ovarian cancer after excision of endometrioma. (2016)
  • Author(s): Haraguchi H, Koga K, Takamura M, Makabe T, Sue F, Miyashita M, Urata Y, Izumi G, Harada M, Hirata T, Hirota Y, Wada-Hiraike O, Oda K, Kawana K, Fujii T, Osuga Y.
  • Journal Title: Fertil Steril Volume: 106 Pages: 1432-1437
  • DOI: 10.1016/j.fertnstert.2016.07.1077.
  • Peer Reviewed
• [Journal Article] Autophagy inhibition augments resveratrol-induced apoptosis in Ishikawa endometrial cancer cells. (2016)
  • Author(s): Fukuda T, Oda K, Wada-Hiraike O, Sone K, Inaba K, Ikeda Y, Makii C, Miyasaka A, Kashiyama T, Tanikawa M, Arimoto T, Yano T, Kawana K, Osuga Y, Fujii T.
  • Journal Title: Oncol Lett Volume: 12 Pages: 2560-2566
  • Peer Reviewed
• [Journal Article] MDM2 is a potential therapeutic target and prognostic factor for ovarian clear cell carcinomas with wild type TP53. (2016)
  • Author(s): Makii C, Oda K, Ikeda Y, Sone K, Hasegawa K, Uehara Y, Nishijima A, Asada K, Koso T, Fukuda T, Inaba K, Oki S, Machino H, Kojima M, Kashiyama T, Mori-Uchino M, Arimoto T, Wada-Hiraike O, Kawana K, Yano T, Fujiwara K, Aburatani H, Osuga Y, Fujii T.
  • Journal Title: Oncotarget Volume: 7 Pages: 75328-75338
  • DOI: 10.18632/oncotarget.12175.
  • Peer Reviewed
• [Journal Article] STAT3 activity regulates sensitivity to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in cervical cancer cells. (2016)
  • Author(s): Nakamura H, Taguchi A, Kawana K, Kawata A, Yoshida M, Fujimoto A, Ogishima J, Sato M, Inoue T, Nishida H, Furuya H, Tomio K, Eguchi S, Mori-Uchino M, Yamashita A, Adachi K, Arimoto T, Wada-Hiraike O, Oda K, Nagamatsu T, Osuga Y, Fujii T.
  • Journal Title: Int J Oncol Volume: 49 Pages: 2155-2162
  • DOI: 10.3892/ijo.2016.3681.
  • Peer Reviewed
• [Journal Article] Assisted reproductive technology pregnancy complications are significantly associated with endometriosis severity before conception: a retrospective cohort study. (2016)
  • Author(s): Fujii T, Wada-Hiraike O, Nagamatsu T, Harada M, Hirata T, Koga K, Fujii T, Osuga Y.
  • Journal Title: Reprod Biol Endocrinol Volume: 14 Pages: 73
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Art pregnancy complication are significantly associated with endometriosis severity before conception: A retrospective study (2017)
  • Author(s): Osamu Wada-Hiraike, Tatsuya Fujii, Takeshi Nagamatsu, Miyuki Harada, Tetsuya Hirata, Kaori Koga, Tomoyuki Fujii, Yutaka Osuga
  • Organizer: 64th Annual Meeting of the Society for Reproductive Investigation
  • Place of Presentation: 米国（フロリダ）
  • Year and Date: 2017-03-15 – 2017-03-18
  • Int'l Joint Research
• [Presentation] 卵巣における抗老化因子の役割 (2016)
  • Author(s): 平池 修
  • Organizer: 第26回臨床内分泌代謝Update
  • Place of Presentation: 埼玉
  • Year and Date: 2016-11-18 – 2016-11-19
  • Invited
• [Presentation] 日本産科婦人科内視鏡学会の取り組む安全性担保 技術認定制度・施設認定制度・第三者評価委員会 (2016)
  • Author(s): 平池 修
  • Organizer: 第56回 日本産科婦人科内視鏡学会 学術講演会
  • Place of Presentation: 長崎
  • Year and Date: 2016-09-01 – 2016-09-04
  • Invited
• [Presentation] 指導者の立場からみた腹腔鏡下子宮全摘術の安全な遂行 (2016)
  • Author(s): 平池 修
  • Organizer: 第56回 日本産科婦人科内視鏡学会 学術講演会
  • Place of Presentation: 長崎
  • Year and Date: 2016-09-01 – 2016-09-04
  • Invited