The study on the effect of the GHRH antagonist on gynecological tumor and ovarian function

2008 Fiscal Year Final Research Report

• Project/Area Number: 19591890
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: The University of Tokyo
• Principal Investigator: YANO Tetsu The University of Tokyo, 医学部・附属病院, 准教授 (90251264)
• Co-Investigator(Kenkyū-buntansha): NAKAGAWA Shunsuke 東京大学, 医学部・附属病院, 助教 (70270874)
• Project Period (FY): 2007 – 2008
• Keywords: GHRH / GHRHアンタゴニスト / 子宮内膜癌 / 子宮内膜症 / 細胞周期 / アポトーシス

Research Abstract

GHRHとその受容体は中枢のみならず末梢組織での発現が報告されている。 新規GHRHアンタゴニストMZ-5-156の子宮内膜癌細胞株HEC-1Aに対する直接的増殖抑制効果とそのメカニズムについてアポトーシスの観点より検討した。GHRHアンタゴニストMZ-5-156によるヒト子宮内膜癌細胞に対する直接的増殖抑制効果が認められた。このメカニズムの一つとして、p53、p53AIP1、Fas、caspase3の活性を増強しBcl-2の活性を減少することによりアポトーシスが誘導されることが示唆された。また、子宮内膜症の病態におけるGHRH およびGHRH のSV1受容体の関与について検討し、子宮内膜症病変のGHRHが局所因子として子宮内膜症の発症・進展に影響を与えている可能性とGHRHアンタゴニストによる子宮内膜症の局所的治療法の可能性が示唆された。

Research Products

• [Journal Article] Interleukin-4 induces expression of eotaxin in endometriotic stromal cells (2009)
  • Author(s): Ouyang Z, Osuga Y, Hirota Y, Hirata T, Yoshino O, Koga K, Yano T, Taketani Y.
  • Journal Title: Fertil Steril (in press)
  • Peer Reviewed
• [Journal Article] Glypican-3 expression in clear cell adenocarcinoma of the ovary (2009)
  • Author(s): Maeda D, Ota S, Takazawa Y, AburataniH, Nakagawa S, Yano T, Taketani Y,Kodama T, Fukayama M.
  • Journal Title: Mod Pathol (in press)
  • Peer Reviewed
• [Journal Article] Elevated serum soluble fms-like tyrosine kinase 1(sFlt1)level in women with hydatidiform mole (2009)
  • Author(s): Koga K, Osuga Y, Tajima T, Hirota Y, Igarashi T, Fujii T, Yano T, Taketani Y.
  • Journal Title: Fertil Steril (in press)
  • Peer Reviewed
• [Journal Article] Expression and regulation of cholesterol sulfotransferase(SULT2B1b)in human endometrium (2009)
  • Author(s): Koizumi M, Momoeda M, Hiroi H, Hosokawa Y, Tsutsumi R, Osuga Y, YanoT, Taketani Y.
  • Journal Title: Fertil Steril (in press)
  • Peer Reviewed
• [Journal Article] Induction of early decidualization by cadmium, a major contaminant of cigarette smoke (2009)
  • Author(s): Tsutsumi R, Hiroi H, Momoeda M, Hosokawa Y, Nakazawa F, Yano T,Tsutsumi O, Taketani Y.
  • Journal Title: Fertil Steril (in press)
  • Peer Reviewed
• [Journal Article] Bone morphogenetic protein 7(BMP-7)increases the expression of follicle-stimulating hormone(FSH)receptor in human granulosa cells (2009)
  • Author(s): Shi J, Yoshino O, Osuga Y, Nishii O, Yano T, Taketani Y.
  • Journal Title: Fertil Steril (in press)
  • Peer Reviewed
• [Journal Article] Expression and possible implication of growth hormone-releasing hormone receptor splice variant 1 in endometriosis (2009)
  • Author(s): Fu L, Osuga Y, Yano T, Takemura Y, Morimoto C, Hirota Y, Schally AV, Taketani Y.
  • Journal Title: Fertil Steril (in press)
  • Peer Reviewed
• [Journal Article] Conjoined twins in a triplet pregnancy after intracytoplasmic sperm injection and blastocyst transfer : case report and review of the literature (2009)
  • Author(s): Hirata T, Osuga Y, Fujimoto A, OishiH, Hiroi H, Fujiwara T, Yano T, Taketani Y.
  • Journal Title: Fertil Steril 91:933 Pages: e9-12
  • Peer Reviewed
• [Journal Article] Co-activation of ER{beta} by agonadotropin-induced cofactor GIOT-4 (2009)
  • Author(s): Kouzu-Fujita M, Mezaki Y, Sawatsubashi S, Matsumoto T, YamaokaI, Yano T, Taketani Y, Kitagawa H, Kato S.
  • Journal Title: Mol Cell Biol 29 Pages: 83-92
  • Peer Reviewed
• [Journal Article] Tunicamycin enhances the apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand in endometriotic stromal cells (2009)
  • Author(s): Hasegawa A, Osuga Y, Hirota Y,Hamasaki K, Kodama A, Harada M, TajimaT, Takemura Y, Hirata T, Yoshino O, Koga K, Yano T, Taketani Y.
  • Journal Title: Hum Reprod 24 Pages: 408-414
  • Peer Reviewed
• [Journal Article] IL-1{beta} stimulates migration and survival of first trimester villous cytotrophoblast cells through endometrial epithelialcell-derived IL-8 (2009)
  • Author(s): Hirota Y, Osuga Y, Hasegawa A, KodamaA, Tajima T, Hamasaki K, Koga K, Yoshino O, Hirata T, Harada M, Takemura Y, Yano T, Tsutsumi O, Taketani Y.
  • Journal Title: Endocrinology 150 Pages: 350-356
  • Peer Reviewed
• [Journal Article] Androgen insensitivity syndrome with serous gonadal cyst (2008)
  • Author(s): Yanai Y, Hiroi H, Osuga Y, Fujimoto A, Momoeda M, Yano T, Taketani Y.
  • Journal Title: Fertil Steril 90 Pages: 2018.e9-11
  • Peer Reviewed
• [Journal Article] Interleukin-4 stimulates proliferation of endometriotic stromal cells (2008)
  • Author(s): OuYang Z, Hirota Y, Osuga Y, HamasakiK, Hasegawa A, Tajima T, Hirata T, KogaK, Yoshino O, Harada M, Takemura Y, Nose E, Yano T, Taketani Y.
  • Journal Title: Am J Pathol 173 Pages: 463-469
  • Peer Reviewed
• [Journal Article] hScrib, a human homologue of Drosophila neoplastic tumor suppressor, is a novel death substrate targeted by caspase during the process of apoptosis (2008)
  • Author(s): Sone K, Nakagawa S, Nakagawa K,Takizawa S, Matsumoto Y, Nagasaka K, Tsuruga T, Hiraike H, Hiraike-Wada O, Miyamoto Y, Oda K, Yasugi T, Kugu K, Yano T, Taketani Y.
  • Journal Title: Genes Cells 13 Pages: 771-785
  • Peer Reviewed
• [Journal Article] Inhibitory Effects of cholesterol sulfate on progesterone production in human granulosa-like tumor cell line, KGN (2008)
  • Author(s): Tsutsumi R, Hiroi H, Momoeda M, Hosokawa Y, Nakazawa F, Koizumi M,Yano T, Tsutsumi O, Taketani Y.
  • Journal Title: Endocr J 55 Pages: 575-581
  • Peer Reviewed
• [Journal Article] Dienogest inhibits BrdU uptake withG(0)/G(1) arrest in cultured endometriotic stromal cells (2008)
  • Author(s): Fu L, Osuga Y, Morimoto C, Hirata T, Hirota Y, Yano T, Taketani Y.
  • Journal Title: FertilSteril 89 Suppl 3 Pages: 1344-1347
  • Peer Reviewed
• [Journal Article] High soluble CD44 concentration in peritoneal fluid in endometriosis (2008)
  • Author(s): Hasegawa A, Yoshino O, Osuga Y, HirataT, Yano T, Taketani Y.
  • Journal Title: Fertil Steril 89 Pages: 1267-1268
  • Peer Reviewed
• [Journal Article] Analysis of the status of a novel estrogen receptor α(ERα)coactivator, p72, in indometrial cancer and its cross talk with erbB-2 in the transactivation of Erα (2008)
  • Author(s): Zhao L, Watanabe M, Yano T, YanagisawaJ, Nakagawa S, Oishi H, Wada-HiraikeO, Oda K, Minaguchi T, Yasugi T, KatoS, Taketani Y.
  • Journal Title: Molecular Medicine Reports 1 Pages: 387-390
  • Peer Reviewed
• [Journal Article] Expression and regulation of periostin/OSF-2 gene in rat uterus and human endometrium (2008)
  • Author(s): Hiroi H, Momoeda M, Nakazawa F, Koizumi M, Tsutsumi R, Hosokawa Y, Osuga Y, Yano T, Tsutsumi O, Taketani Y.
  • Journal Title: Endocr J 55 Pages: 183-189
  • Peer Reviewed
• [Journal Article] Evidence for the expression of alcohol dehydrogenase class I gene in rat uterus and its up-regulation by progesterone (2008)
  • Author(s): Ohno T, Hiroi H, Momoeda M, HosokawaY, Tsutsumi R, Koizumi M, Nakazawa F, Yano T, Tsutsumi O, Taketani Y.
  • Journal Title: Endocr J 55 Pages: 83-90
  • Peer Reviewed
• [Journal Article] Cellular mechanisms of growth inhibition of human endometrial cancer cell line by an antagonist of growth hormone-releasing hormone (2008)
  • Author(s): Zhao L, Yano T, Osuga Y, Nakagawa S, Oishi H, Wada-Hiraike O, Tang X, YanoN, Kugu K, Schally AV, Taketani Y.
  • Journal Title: IntJ Oncol 32 Pages: 593-601
  • Peer Reviewed
• [Journal Article] Interleukin(IL)-17A stimulates IL-8 secretion, COX2 expression, and cell proliferation of endometriotic stromal cells (2008)
  • Author(s): Hirata T, Osuga Y, Hamasaki K, YoshinoO, Ito M, Hasegawa A, Takemura Y, Hirota Y, Nose E, Morimoto C, HaradaM, Koga K, Tajima T, Saito S, Yano T, Taketani Y.
  • Journal Title: Endocrinology 149 Pages: 1260-1267
  • Peer Reviewed
• [Journal Article] Gonadotropin-inhibitory hormone and its receptor in the avian reproductive system (2008)
  • Author(s): Bentley GE, Ubuka T, McGuire NL, Chowdhury VS, Morita Y, Yano T,Hasunuma I, Binns M, Wingfield JC, Tsutsui K.
  • Journal Title: Gen Comp Endocrinol 156 Pages: 34-43
  • Peer Reviewed
• [Journal Article] Loss of Hugl-1expression associates with lymph nodemetastasis in endometrial cancer (2007)
  • Author(s): Tsuruga T, Nakagawa S, Watanabe M,Takizawa S, Matsumoto Y, Nagasaka K,Sone K, Hiraike H, Miyamoto Y, HiraikeO, Minaguchi T, Oda K, Yasugi T, YanoT, Taketani Y.
  • Journal Title: Oncol Res 16 Pages: 431-435
  • Peer Reviewed
• [Journal Article] Human papillomavirus type 16 P(670)promoter is negatively regulated by CCAAT displacement protein (2007)
  • Author(s): Sato K, Takeuchi T, Kukimoto I, MoriS, Yasugi T, Yano T, Taketani Y, Kanda T.
  • Journal Title: Virus Genes 35 Pages: 473-481
  • Peer Reviewed
• [Journal Article] The presence of midkine and its possible implication in human ovarian follicles (2007)
  • Author(s): Hirota Y, Osuga Y, Nose E, Koga K, Yoshino O, Hirata T, Yano T, TsutsumiO, Sakuma S, Muramatsu T, Taketani Y.
  • Journal Title: Am J Reprod Immunol 58 Pages: 367-373
  • Peer Reviewed
• [Journal Article] Metformin suppresses interleukin(IL)-1beta-induced IL-8 production, aromatase activation, and proliferation of endometriotic stromal cells (2007)
  • Author(s): Takemura Y, Osuga Y, Yoshino O,Hasegawa A, Hirata T, Hirota Y, NoseE, Morimoto C, Harada M, Koga K, TajimaT, Yano T, Taketani Y.
  • Journal Title: J Clin Endocrinol Metab 92 Pages: 3213-3218
  • Peer Reviewed
• [Journal Article] Expression of toll-like receptors 2, 3, 4, and 9 genes in the human endometrium during the menstrual cycle (2007)
  • Author(s): Hirata T, Osuga Y, Hamasaki K, HirotaY, Nose E, Morimoto C, Harada M, Takemura Y, Koga K, Yoshino O, TajimaT, Hasegawa A, Yano T, Taketani Y.
  • Journal Title: J Reprod Immunol 74(1-2) Pages: 53-60
  • Peer Reviewed
• [Presentation] 宮内膜症の疼痛管理 (2008)
  • Author(s): 矢野哲子
  • Organizer: 宮崎市郡産婦人科医会研修会特別講演
  • Place of Presentation: 宮崎
  • Year and Date: 2008-11-20
• [Presentation] ショウジョウバエの癌抑制蛋白scribbleのヒトホモログであるhScribはアポトーシス時カスパーゼによって分解される (2008)
  • Author(s): 曽根献文、中川俊介、鶴賀哲史、長阪一憲、松本陽子、滝澤慎、八杉利治、矢野哲、武谷雄二
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-29
• [Presentation] PIK3CA遺伝子変異とRas遺伝子変異の共存は、Rasによるtransformationを効率的に誘導する (2008)
  • Author(s): 織田克利、Jennifer Okada、庄司恵子、中川俊介、川名敬、矢野哲、武谷雄二
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-29
• [Presentation] PI3K経路に変異を有さない子宮体癌の臨床的特徴と予後不良因子としての可能性 (2008)
  • Author(s): 庄司恵子、織田克利、細川さつき、中川俊介、川名敬、根井朝美、上原ゆり子、油谷浩幸、矢野哲、武谷雄二
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-29
• [Presentation] モデルマウスを用いたエストロゲン受容体(ER)・の子宮内膜症発症における機能解析 (2008)
  • Author(s): 平池修、矢野哲、大須賀穣、平田哲也、武谷雄二
  • Organizer: 第53回日本生殖医学会学術講演会
  • Place of Presentation: 神戸
  • Year and Date: 2008-10-23
• [Presentation] エストロゲン受容体(ER)・の子宮内膜症発症における機能解析 (2008)
  • Author(s): 平池修、矢野哲、平池春子、大須賀穣、平田哲也、中川俊介、武谷雄二
  • Organizer: 第26回日本受精着床学会学術講演会
  • Place of Presentation: 福岡
  • Year and Date: 2008-08-28
• [Presentation] 子宮内膜症の疼痛管理江戸川、江東 (2008)
  • Author(s): 矢野哲
  • Organizer: 千葉西ブロック産婦人科医会合同卒後研修会教育講演
  • Place of Presentation: 東京
  • Year and Date: 2008-07-16
• [Presentation] 子宮内膜症の管理 (2008)
  • Author(s): 矢野哲
  • Organizer: 市川市医師会産婦人科医会研修会特別講演
  • Place of Presentation: 市川
  • Year and Date: 2008-07-10
• [Presentation] Cellular mechanisms of growth inhibition of human endometrial cancer cell line by type II GnRH (2008)
  • Author(s): Yano T, Zhao L, Osuga Y, Nakagawa S, Oishi H, Wada-Hiraike O, Matsumi H, Yano N, Kugu K, Taketani Y
  • Organizer: 90^<th> Annual Meeting of the Endocrine Society
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2008-06-17
• [Presentation] Cholesterol Sulfate Regulates the Classical wnt Pathway in Human Endometrium (2008)
  • Author(s): Nakazawa F, Momoeda M, Hiroi H, Tsutsumi R, Hosokawa Y, Koizumi M, YanoT, Tsutsumi O, Taketani Y
  • Organizer: 90^<th> Annual Meeting of the Endocrine Society
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2008-06-17
• [Presentation] Expression and Regulation of Hsp70 Interacting Protein Hip in Human and Rat Utreus (2008)
  • Author(s): Hosokawa Y, Hiroi H, Momoeda M, Tsutsumi R, Nakazawa F, Koizumi M, YanoT, Tsutsumi O, Taketani Y
  • Organizer: 90^<th> Annual Meeting of the Endocrine Society
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2008-06-17
• [Presentation] 子宮内膜症の疼痛管理 (2008)
  • Author(s): 矢野哲
  • Organizer: 金沢市産婦人科医会講演会特別講演
  • Place of Presentation: 金沢
  • Year and Date: 2008-05-15
• [Presentation] HPV E6新規標的DBC-1(乳癌関連遺伝子)のアポトーシスへの関与 (2008)
  • Author(s): 曽根献文、中川俊介、滝澤慎、松本陽子、長阪一憲、鶴賀哲史、平池春子、宮本雄一郎、八杉利治、矢野哲、武谷雄二
  • Organizer: 第60回日本産科婦人科学会学術講演会
  • Place of Presentation: 横浜
  • Year and Date: 2008-04-14
• [Presentation] 子宮体癌のPI3K経路活性化におけるp110α isoformの優位性 (2008)
  • Author(s): 織田克利、八杉利治、川名敬、中川俊介、蔵本博行、藤井知行、矢野哲、武谷雄二
  • Organizer: 第60回日本産科婦人科学会学術講演会
  • Place of Presentation: 横浜
  • Year and Date: 2008-04-14
• [Presentation] ショウジョウバエ癌抑制蛋白LglのヒトホモログであるHugl-1はadherensjunctionの架橋蛋白であるLMO7と結合する (2008)
  • Author(s): 鶴賀哲史、中川俊介、平池春子、宮本雄一郎、曽根献文、長阪一憲、松本陽子、瀧澤慎、八杉利治、矢野哲、武谷雄二
  • Organizer: 第60回日本産科婦人科学会学術講演会
  • Place of Presentation: 横浜
  • Year and Date: 2008-04-14
• [Presentation] 極性保持に関与する癌抑制蛋白Hugl-1の結合蛋白としてのSH3BP2の同定 (2008)
  • Author(s): 平池春子、中川俊介、平池修、瀧澤慎、松本陽子、長阪一憲、鶴賀哲史、曽根献文、宮本雄一郎、八杉利治、矢野哲、武谷雄二
  • Organizer: 第60回日本産科婦人科学会学術講演会
  • Place of Presentation: 横浜
  • Year and Date: 2008-04-14
• [Presentation] 子宮内膜症におけるTh17の発現とその意義 (2008)
  • Author(s): 平田哲也、大須賀穣、濱崎かほり、吉野修、原田美由紀、長谷川亜希子、田島敏樹、児玉亜子、伊藤美香、斉藤滋、矢野哲、武谷雄二
  • Organizer: 第60回日本産科婦人科学会学術講演会
  • Place of Presentation: 横浜
  • Year and Date: 2008-04-14
• [Presentation] 子宮内膜症の疼痛管理 (2008)
  • Author(s): 矢野哲
  • Organizer: 北信産婦人科医会学術講演会特別講演
  • Place of Presentation: 長野
  • Year and Date: 2008-03-24
• [Presentation] Growth Inhibition of Human Endometrial Cancer Cell Line by Type II GnRH (2008)
  • Author(s): Yano T, Zhao L, Osuga Y, Nakagawa S, Oishi H, Wada-Hiraike O, Tang X, YanoN, Kugu K, Taketani Y
  • Organizer: 9th International Symposium on GnRH Analogues in Cancer and Human Reproduction
  • Place of Presentation: Berlin, Germany
  • Year and Date: 2008-02-11
• [Presentation] Clomiphene combined with flexible multidose GnRH antagonist for patients with poor prognosis in IVF-ET programs (2008)
  • Author(s): Oishi H, Yano T, Fujimoto A, Hirata T, Fujiwara T, Taketani Y
  • Organizer: 9th International Symposium on GnRH Analogues in Cancer and Human Reproduction
  • Place of Presentation: Berlin, Germany
  • Year and Date: 2008-02-11
• [Presentation] Inhibitory effect of an antagonist of growth hormone-releasing hormone on the growth of human endometrial cancer cell lines in vitro (2007)
  • Author(s): Yano T, Zhao L, Osuga Y, Nakagawa S, Oishi H, Wada-Hiraike O, Tang X, YanoN, Kugu K, Schally AV, Taketani Y
  • Organizer: Oxford-Kobe Seminar Biomedical Science-International Symposium on Translational Research in Uterine Biology
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2007-11-29
• [Presentation] The role of bone morphogenetic protein-7(BMP-7)in the humanendometrium (2007)
  • Author(s): Yoshino O, Osuga Y, Yano T, Taketani Y
  • Organizer: 63^<rd> Annual Meeting of the American Society of Reproductive Medicine
  • Place of Presentation: Washington D. C., USA
  • Year and Date: 2007-10-15
• [Presentation] Interleukin-17 stimulates the proliferation and IL-8 secretion from endometriotic stromal cells (2007)
  • Author(s): Hirata T, Osuga Y, Yano T, Tsutsumi O, Taketani Y
  • Organizer: 63^<rd> Annual Meeting of theAmerican Society of Reproductive Medicine
  • Place of Presentation: Washington D. C., USA,
  • Year and Date: 2007-10-15
• [Presentation] エストロゲンレセプター(ER)βックアウトマウス(βERKO)における大腸の表現型解析 (2007)
  • Author(s): 平池修、矢野哲、平池春子、武谷雄二
  • Organizer: 第80回日本内分泌学会学術総会
  • Place of Presentation: 東京
  • Year and Date: 2007-06-15
• [Presentation] 生涯研修プログラムクリニカルカンファランス(生殖内分泌領域)最新の子宮内膜症管理2)慢性骨盤痛への対処 (2007)
  • Author(s): 矢野哲
  • Organizer: 第59回日本産科婦人科学会総会・学術講演会
  • Place of Presentation: 東京
  • Year and Date: 2007-04-14
• [Book] GnRHアナログ : 産婦人科研修ノート(三橋直樹編) (2009)
  • Author(s): 矢野哲
  • Total Pages: 212-214
  • Publisher: 診断と治療社
• [Book] Inhibitory effect of an antagonist of growth hormone-releasing hormone on the growth of human endometrial cancer cell lines in vitro. In Translational Research in Uterine Biolpgy. Proceeding of the Kobe-Oxford International Symposium held in Kobe, 28-30 November2007. (2008)
  • Author(s): Yano T, Zhao L, Osuga Y, Nakagawa S, Oishi H, Wada-Hiraike O, Tang X, Yano N,Kugu K, Schally AV, Taketani Y.
  • Total Pages: 201-211
  • Publisher: Eds. Maruo T, Mardom H and StewartC. Elsevier
• [Book] 不正性器出血 : 看護に役立つ疾患・症候事典(永井良三編) (2008)
  • Author(s): 矢野哲
  • Total Pages: 586-1588
  • Publisher: メヂカルフレンド社
• [Book] 子宮筋腫 : 腹痛診療ナビ(神保勝一編) (2008)
  • Author(s): 矢野哲
  • Total Pages: 289-292
  • Publisher: 日本医事新報社
• [Book] 子宮内膜症今日の治療指針2007年版 (2007)
  • Author(s): 矢野哲
  • Total Pages: 887-888
  • Publisher: 医学書院子
• [Book] 不育症の検査-内分泌・代謝因子生殖医療ガイドライン2007(日本生殖医学会編) (2007)
  • Author(s): 矢野哲
  • Total Pages: 277-278
  • Publisher: 金原出版