Analysis to elucidate regulatory mechanism of LXR in uterine tissue

• Project/Area Number: 24592505
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: The University of Tokyo
• Principal Investigator: HIRAIKE Osamu 東京大学, 医学部附属病院, 講師 (20529060)
• Co-Investigator(Kenkyū-buntansha): ODA Katsutoshi 東京大学医学部附属病院, 女性外科, 准教授 (30359068) ; 織田 克利 東京大学, 医学部附属病院, 准教授 (30359608)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 核内受容体 / 転写因子 / 乳がん / 子宮体がん / 脂質代謝 / 癌抑制遺伝子 / 転写制御 / 子宮内膜

Outline of Final Research Achievements

Liver X receptors (LXRs) have been shown to maintain whole-body cholesterol level. Recent studies demonstrate that LXRs might inhibit cellular proliferation, but the underlying mechanism remains to be elucidated.
We found that CCAR2 could form a complex with LXRα in a ligand-independent manner in HepG2 cells, and in vitro pull down assays revealed a direct interaction between the amino-terminus of CCAR2 and AF-2 domain of LXRα. Thereby CCAR2 attenuates the ligand-dependent transcriptional activation function of LXRα. Abrogation of CCAR2 resulted in a decreased cellular proliferation. Competitive immunoprecipitation studies have revealed that the downregulation of LXRα involves inhibition of SIRT1 interaction with LXRα. These results clearly indicate the mechanism that CCAR2 might regulate the transcriptional activation function of LXRα due to its specific inhibition of SIRT1 and serve to regulate the cellular proliferation.

Research Products

• [Journal Article] A coexistence case of right tubal adenomyoma and ectopic pregnancy (2015)
  • Author(s): Miyasaka A, Wada-Hiraike O, Shiotsu H, Osuga Y, Fujii T.
  • Journal Title: J Minim Invasive Gynecol Volume: 22 Issue: 1 Pages: 6-6
  • DOI: 10.1016/j.jmig.2014.05.009
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Temporary balloon occlusion of the uterine arteries to control hemorrhage during hysterectomy in a case of uterine arteriovenous fistula (2015)
  • Author(s): Yamamoto N, Koga K, Akahane M, Wada-Hiraike O, Fujii T, Osuga Y
  • Journal Title: J Obstet Gynaecol Res Volume: 41 Issue: 2 Pages: 314-318
  • DOI: 10.1111/jog.12515
  • Peer Reviewed
• [Journal Article] Identifying patients who can improve fertility with myomectomy. (2015)
  • Author(s): Samejima T, Koga K, Nakae H, Wada-Hiraike O, Fujimoto A, Fujii T, Osuga Y
  • Journal Title: Eur J Obstet Gynecol Reprod Biol Volume: 185 Pages: 28-32
  • DOI: 10.1016/j.ejogrb.2014.11.033
  • Peer Reviewed
• [Journal Article] CCAR2 negatively regulates nuclear receptor LXRα by competing with SIRT1 deacetylase. (2015)
  • Author(s): Sakurabashi A, Wada-Hiraike O, Hirano M, Fu H, Isono W, Fukuda T, Morita Y, Tanikawa M, Miyamoto Y, Oda K, Kawana K, Osuga Y, Fujii T.
  • Journal Title: J Steroid Biochem Mol Biol Volume: 149 Pages: 80-88
  • DOI: 10.1016/j.jsbmb.2015.02.001
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Concomitant ovarian drilling and oocyte retrieval by laparoendoscopic single-site surgery led to live birth using in vitro maturation of oocyte and transfer of frozen-thawed blastocyst in woman with polycystic ovary syndrome. (2014)
  • Author(s): Hirata T, Fujimoto A, Koga K, Wada-Hiraike O, Fujii T, Osuga Y.
  • Journal Title: J Obstet Gynaecol Res Volume: 40 Issue: 5 Pages: 1431-1435
  • DOI: 10.1111/jog.12365
  • Peer Reviewed
• [Journal Article] SIRT3 positively regulates the expression of folliculogenesis- and luteinization-related genes and progesterone secretion by manipulating oxidative stress in human luteinized granulosa cells. (2014)
  • Author(s): Fu H, Wada-Hiraike O, Hirano M, Kawamura Y, Sakurabashi A, Shirane A, Morita Y, Isono W, Oishi H, Koga K, Oda K, Kawana K, Yano T, Kurihara H, Osuga Y, Fujii T.
  • Journal Title: Endocrinology Volume: 155 Issue: 8 Pages: 3079-3087
  • DOI: 10.1210/en.2014-1025
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Oral vaccination against HPV E7 for treatment of cervical intraepithelial neoplasia grade 3 (CIN3) elicits E7-specific mucosal immunity in the cervix of CIN3 patients (2014)
  • Author(s): Kawana K, Adachi K, Kojima S, Taguchi A, Tomio K, Yamashita A, Nishida H, Nagasaka K, Arimoto T, Yokoyama T, Wada-Hiraike O, Oda K, Sewaki T, Osuga Y, Fujii T
  • Journal Title: Vaccine Volume: 32 Issue: 47 Pages: 6233-6239
  • DOI: 10.1016/j.vaccine.2014.09.020
  • Peer Reviewed
• [Journal Article] Factors that predict poor clinical course among patients hospitalized with pelvic inflammatory disease (2014)
  • Author(s): Terao M, Koga K, Fujimoto A, Wada-Hiraike O, Osuga Y, Yano T, Kozuma S
  • Journal Title: Journal of Obstetrics and Gynaecolgic Research Volume: 40 Pages: 495-500
  • Peer Reviewed
• [Journal Article] Resveratrol suppresses inflammatory responses in endometrial stromal cells derived from endometriosis: A possible role of the sirtuin 1 pathway (2014)
  • Author(s): Taguchi A, Wada-Hiraike O, Kawana K, Koga K, Yamashita A, Shirane A, Urata Y, Kozuma S, Osuga Y, Fujii T
  • Journal Title: J Obstet Gynaecol Res Volume: 40 Issue: 3 Pages: 770-8
  • DOI: 10.1111/jog.12252
  • Peer Reviewed
• [Journal Article] Anti-tumor activity of olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in cultured endometrial carcinoma cells. (2014)
  • Author(s): A. Miyasaka, K. Oda, Y. Ikeda, O. Wada-Hiraike, T. Kashiyama, A. Enomoto, N. Hosoya, T. Koso, T. Fukuda, K. Inaaba, K. Sone, Y. Uehara, R. Kurikawa, K. Nagasaka, Y.Matsumoto, T. Arimoto, S. Nakagawa, H. Kuramoto, K. Miyagawa, T. Yano, K. Kawana, Y. Osuga, T. Fujii.
  • Journal Title: BMC Cancer Volume: - Issue: 1 Pages: 179-179
  • DOI: 10.1186/1471-2407-14-179
  • Peer Reviewed
• [Journal Article] Matrix metalloproteinase (MMP)-9 in cancer-associated fibroblasts (CAFs) is suppressed by omega-3 polyusaturated fatty acids in vitro and in vivo. (2014)
  • Author(s): Taguchi A, Kawana K, Tomio K, Yamashita A, Isobe Y, Nagasaka K, Koga K, Inoue T, Nishida H, kojima S, Adachi K, Matsumoto Y, Arimoto T, Wada-Hiraike O, Oda K, kang JX, Arai H, Arita M, Osuga Y, Fujii T.
  • Journal Title: PLoS One Volume: 27 Issue: 2 Pages: e89605-e89605
  • DOI: 10.1371/journal.pone.0089605
  • Peer Reviewed
• [Journal Article] Antitumor Activity and Induction of TP53-Dependent Apoptosis toward Ovarian Clear Cell Adenocarcinoma by the Dual PI3K/mTOR Inhibitor DS-7423. (2014)
  • Author(s): Kashiyama T, Oda K, Ikeda Y, Shiose Y, Hirota Y, Inaba K, Makii C, Kurikawa R, Miyasaka A, Koso T, Fukuda T, Tanikawa M, Shoji K, Sone K, Arimoto T, Wada-Hiraike O, Kawana K, Nakagawa S, Matsuda K, McCormick F, Aburatani H, Yano T, Osuga Y, Fujii T
  • Journal Title: PLoS One Volume: 9 Issue: 2 Pages: e87220-e87220
  • DOI: 10.1371/journal.pone.0087220
  • Peer Reviewed
• [Journal Article] Role of multifunctional transcription factor TFII-I and putative tumour suppressor DBC1 in cell cycle and DNA double strand damage repair. (2013)
  • Author(s): Tanikawa M, Wada-Hiraike O, Yoshizawa-Sugata N, Shirane A, Hirano M, Hiraike H, Miyamoto Y, Sone K, Ikeda Y, Kashiyama T, Oda K, Kawana K, Katakura Y, Yano T, Masai H, Roy AL, Osuga Y, Fujii T
  • Journal Title: British Journal of Cancer Volume: 109 Pages: 3042-3048
  • Peer Reviewed
• [Journal Article] Increased tissue level of omega-3 polyunsaturated fatty acids prevents pathological preterm birth. (2013)
  • Author(s): Yamashita A, Kawana K, Tomio K, Taguchi A, Isobe Y, Iwamoto R, Masuda K, Furuya H, Nagamatsu T, Nagasaka K, Oda K, Wada-Hiraike O, Yamashita T, Taketani Y, Kang JX, Arai H, Arita M, Kozuma S, Fujii T.
  • Journal Title: Sci Rep Volume: 3 Issue: 1 Pages: 3113-3113
  • DOI: 10.1038/srep03113
  • Peer Reviewed
• [Journal Article] Laparoscopic ovarian-sparing surgery for a young woman with an exophytic ovarian fibroma (2013)
  • Author(s): Hasegawa A1, Koga K, Asada K, Wada-Hiraike O, Osuga Y, Kozuma S.
  • Journal Title: J Obstet Gynaecol Res. Volume: 39 Issue: 12 Pages: 1610-3
  • DOI: 10.1111/jog.12107
  • Peer Reviewed
• [Journal Article] Sequential effects of the proteasome inhibitor bortezomib and chemotherapeutic agents in uterine cervical cancer cell lines. (2013)
  • Author(s): Miyamoto Y, Nakagawa S, Wada-Hiraike O, Seiki T, Tanikawa M, Hiraike H, Sone K, Nagasaka K, Oda K, Kawana K, Nakagawa K, Fujii T, Yano T, Kozuma S, Taketani Y.
  • Journal Title: Oncol Rep. Volume: 29(1) Issue: 1 Pages: 51-7
  • DOI: 10.3892/or.2012.2072
  • Peer Reviewed
• [Journal Article] The prevalence of cervical regulatory T cells in HPV-related cervical intraepithelial neoplasia (CIN) correlates inversely with spontaneous regression of CIN (2013)
  • Author(s): Kojima S, Kawana K, Tomio K, Yamashita A, Taguchi A, Nagamatsu T, Nagasaka K, Matsumoto Y, Arimoto T, Oda K, Wada-Hiraike O, Yano T, Taketani Y, Fujii T, Schust DJ, Kozuma S
  • Journal Title: Am J Reprod Immunol, Volume: 69 Issue: 2 Pages: 134-144
  • DOI: 10.1111/aji.12030
  • Peer Reviewed
• [Journal Article] Spontaneous cessation and recurrence of massive uterine bleeding can occur in uterine artery (2013)
  • Author(s): Hajime Oishi
  • Journal Title: J Obstet Gynaecol Res. Volume: 39(2) Issue: 2 Pages: 598-602
  • DOI: 10.1111/j.1447-0756.2012.01993.x
  • Peer Reviewed
• [Journal Article] Uterine arteriovenous fistula treated with repetitive transcatheter embolization:case report. (2012)
  • Author(s): Hasegawa A
  • Journal Title: Journal of Minimally Invasive Gynecology Volume: 19(6) Issue: 6 Pages: 780-4
  • DOI: 10.1016/j.jmig.2012.07.004
  • Peer Reviewed
• [Journal Article] Regulation of SIRT1 determines initial step of endometrial receptivity by controlling E-cadherin expression (2012)
  • Author(s): Shirane A, Wada-Hiraike O, Tanikawa M, Seiki T, Hiraike H, Miyamoto Y, Sone K, Hirano M, Oishi H, Oda K, Kawana K, Nakagawa S, Osuga Y, Fujii T, Yano T, Kozuma S, Taketani Y
  • Journal Title: Biochem Biophys Res Commun Volume: 424 Issue: 3 Pages: 604-10
  • DOI: 10.1016/j.bbrc.2012.06.160
  • Peer Reviewed
• [Journal Article] Genome-wide single nucleotide polymorphism arrays as a diagnostic tool in patients with synchronous endometrial and ovarian cancer. (2012)
  • Author(s): Ikeda Y, Oda K, Nakagawa S
  • Journal Title: Int J Gynecol Cancer Volume: 22(5） Issue: 5 Pages: 725-31
  • DOI: 10.1097/igc.0b013e31824c6ea6
  • Peer Reviewed
• [Journal Article] Diameter of dominant leiomyoma is a possible determinant to predict coexistent endometriosis (2012)
  • Author(s): Isono W, Wada-Hiraike O, Osuga Y, Yano T, Taketani Y
  • Journal Title: Eur J Obstet Gynecol Reprod Biol Volume: 162(1) Issue: 1 Pages: 87-90
  • DOI: 10.1016/j.ejogrb.2012.01.018
  • Peer Reviewed
• [Presentation] 当院における腹腔鏡下仙骨腟固定術の短期成績 (2015)
  • Author(s): 平池 修
  • Organizer: 第9回骨盤臓器脱手術学会
  • Place of Presentation: 東京
  • Year and Date: 2015-03-06 – 2015-03-08
  • Invited
• [Presentation] エストロゲン標的組織の病態発症に関与する分子制御機構解明を目的とした基礎的研究 (2014)
  • Author(s): 平池 修
  • 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
  • Invited
• [Presentation] 当院における先進医療・腹腔鏡下仙骨腟固定術の現況 (2014)
  • Author(s): 平池 修
  • 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] 当院における先進医療・腹腔鏡下仙骨腟固定術の導入 (2014)
  • Author(s): 平池 修
  • Organizer: 第54回日本産科婦人科内視鏡学会
  • Place of Presentation: 鹿児島
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] Putative tumor suppressor DBC1/CCAR2 negatively regulates the nuclear receptor LXR (2014)
  • Author(s): Osamu Hiraike
  • Organizer: 第96回 ENDO2014 / 第16回 ICE
  • Place of Presentation: 米国 シカゴ
  • Year and Date: 2014-06-20 – 2014-06-24
• [Presentation] Clinical Significance and Pathogenesis of Macroprolactinemia (2013)
  • Author(s): Osamu Hiraike
  • Organizer: 第95回 ENDO2013
  • Place of Presentation: 米国 サンフランシスコ
• [Presentation] AMH高値の多嚢胞性卵巣症候群症例に限定した腹腔鏡下卵巣多孔術 (2013)
  • Author(s): 平池 修
  • Organizer: 第53回日本産科婦人科内視鏡学会
  • Place of Presentation: 名古屋（ウィンクあいち）
• [Presentation] エストロゲン（E）受容体の機能解析と抗老化分子SIRT1のE標的臓器への作用に基いた新規ホルモン補充療法の開発に向けた研究 (2012)
  • Author(s): 平池 修
  • Organizer: 第64回日本産科婦人科学会学術講演会
  • Place of Presentation: 神戸
  • Invited
• [Presentation] 産婦人科領域における抗老化分子SIRT1の生理的作用の解明 (2012)
  • Author(s): 平池 修
  • Organizer: 第14回神澤医学研究振興財団講演会
  • Place of Presentation: 東京
  • Invited
• [Presentation] Resveratrol Promotes Expression of SIRT1 and StAR in Rat Ovarian Granulosa Cells; Possible Implication of SIRT1 in the Ovary (2012)
  • Author(s): Osamu Hiraike
  • Organizer: 第94回 北米内分泌学会
  • Place of Presentation: 米国 ヒューストン
• [Book] 目で見るエストロゲンの生殖器外作用～エストロゲンの抗老化作用～ (2014)
  • Author(s): 平池 修
  • Total Pages: 5
  • Publisher: メジカルビュー社
• [Book] 生殖医療ポケットマニュアル (2014)
  • Author(s): 平池 修
  • Total Pages: 8
  • Publisher: 医学書院
• [Book] 抗加齢物質としてのエストロゲン (2014)
  • Author(s): 平池 修
  • Total Pages: 5
  • Publisher: フジメディカル出版
• [Book] 子宮・腟奇形に対する形成術 (2014)
  • Author(s): 平池 修
  • Total Pages: 7
  • Publisher: 東京医学社
• [Book] 現代生殖医療のメインストリーム 子宮鏡下の不妊症治療 (2014)
  • Author(s): 平池 修
  • Total Pages: 9
  • Publisher: 金原出版
• [Book] 組織特異性を考慮したホルモン補充療法 (2014)
  • Author(s): 平池 修
  • Total Pages: 2
  • Publisher: 協和企画
• [Book] 近年の手術関連機器の進歩 (2013)
  • Author(s): 平池修、大須賀穣、藤井知行
  • Total Pages: 7
  • Publisher: 金原出版
• [Book] 卵巣過剰刺激症候群 ovarian hyperstimulation syndromeの予防と管理 (2013)
  • Author(s): 平池修、矢野哲
  • Total Pages: 7
  • Publisher: 中外医学社
• [Book] 特集：ホルモン療法実践マニュアル GnRHアナログ製剤の種類と特徴 (2012)
  • Author(s): 平池 修
  • Total Pages: 5
  • Publisher: 診断と治療社