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Development of new therapeutic modalities based on the analysis of the pathogenesis and biological features of leiomyoma

Research Project

Project/Area Number 13307047
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Obstetrics and gynecology
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

FUJII Shingo  Kyoto University, Department of Gynecology and Obstetrics, Professor, 医学研究科, 教授 (30135579)

Co-Investigator(Kenkyū-buntansha) NIKAIDO Toshio  Shinshu University, Department of Health, Professor, 医学研究科, 助教授 (50180568)
KARIYA Masatoshi  Kyoto University, Department of Gynecology and Obstetrics, Lecturer, 医学研究科, 講師 (90243013)
FUJITA Jun  Kyoto University, Department of Gynecology and Obstetrics, Professor, 医学研究科, 教授 (50173430)
北 正人  京都大学, 医学研究科, 助手 (50314208)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥49,140,000 (Direct Cost: ¥37,800,000、Indirect Cost: ¥11,340,000)
Fiscal Year 2002: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
Fiscal Year 2001: ¥40,560,000 (Direct Cost: ¥31,200,000、Indirect Cost: ¥9,360,000)
KeywordsUterus / leiomyoma / Ref-1 / mast cell / p53 / sFRP-1 / pathogenesis / treatment / 子宮筋腫 / Wntシグナル / MnSOD / PEP-19 / S100蛋白 / 虚血再還流ストレス / 肥満細胞 / トラニラスト / 子宮平滑筋 / Frizzled related protein 1 / アポトーシス / redox factor 1 / リン酸化 / 翻訳後修飾 / 増殖
Research Abstract

Regarding the proliferation of uterine leiomyoma, the posttranscriptional modification of Ref-1 was revealed to associate with the proliferation of leiomyoma cells in vivo and in vitro. Mast cells in the uterus were suggested to enhance the proliferation of smooth muscle cells. Apoptosis-resistant character of leiomyoma cells was suggested through the studies of sFRP1 (a modulator of Wnt signaling), S100A11 (S100 protein family), and PEP-19. In addition, Ref-1, S100A11, and β catenin were suggested to be involved in the pathophysiology of leiomyosarcoma.
Regarding the pathogenesis of leiomyoma, we hypothesize that leiomyomas resale from proliferation of smooth muscle cells is the myometrial tissue that survives the repeated ischemic-reperfusion stress experienced during the menstrual cycle. The blood supply to the myometrium in vivo is knows to decrease daring uterine contraction, particularly daring menstruation. In each luteal phase of the menstrual cycle, myometrial smooth muscles ex … More hibit proliferative activity, in preparation for pregnancy. However, if pregnancy does not occur, the proliferative activity of the myometrial smooth muscle colts may be interrupted at the time of menstruation. Myometrial contraction, winch results in the cessation of menstrual blinding, probably induces an ischemic / hypoxic state in the myometrial smooth muscle cells. Ischemic injury could occur in these cells which are in the proliferative phase. It is suggested that them injured colts could become candidates for progenitor cells of leiomyomas. Somatic mutation could well be induced in these cells after surviving many repeats of the menstrual cycle. In this respect, immunohistochemically we found e few p53- or p21-positive cells in the myometrium exclusively in the follicular phase of the menstrual cycle. This highly suggests that there exists smooth muscle cells that were injured their DNA during the menses, and these cells would be repaired during the cell-cycle arrest or eliminated through apoptosis. If the cells with injured DNA may acquire apoptosis-resistance expressing molecules such as sFRP1 and S100A11, these cells become the candidates of the precursor of leiomyoma cell.
Regarding the treatment, tranilast that suppresses fibrosis or arts as a mast cell stabilizer, became a candidate of a new therapeutic agent. Tranilast inhibited the proliferation of cultured leiomyoma cells in a dose-dependent manner without any cytotoxic effort. We also demonstrated that uterine arterial embolization successfully reduced the uterine size of diffuse leiomyomatosis, suggesting that this procedure may be a premising new therapeutic modality for this intractable disease without loss of fertility. Less

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (33 results)

All Other

All Publications (33 results)

  • [Publications] Ken Fukuhara, et al.: "Secreted frizzled related protein 1 is overexpressed in uterine leiomyomas, associated with a high estrogenic environment and unrelated to proliferative activity"J Clin Endocrinol Metab.. 87. 1729-1736 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ayaka Orii, et al.: "Altered post-translational modification of redox factor 1 protein in human uterine smooth muscle tumors"J Clin Endocrinol Metab.. 87. 3754-3759 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hiroaki Shime, et al.: "Tranilast Inhibits the Proliferation of Uterine Leiomyoma Cells in Vitro through G1 Arrest Associated with the Induction of p21 (wafl) and p53"J Clin Endocrinol Metab. 87. 5610-5617 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takanobu Kanamori, et al.: "PEP-19 overexpression in human uterine leiomyoma"Mol Hum Reprod. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takashi Kusakari, et al.: "C-erbB-2 or mutant Ha-ras induced malignant transformation of immortalized human ovarian surface epithelial cells in vitro"Eur J Cancer. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Akiko Kido, et al.: "Uterine arterial embolization for the treatment of diffuse leiomyomatosis. A case report"J Vasc Interv Radiol. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ken Fukuhara, Masatoshi Kariya, Masato Kita, Hiroaki Shime, Takanobu Kanamori, Chika Kosaka, Ayaka Orii, Jun Fujita, and Shingo Fujii: "Secreted Frizzled Related Protein 1 Is Overexpressed in Uterine Leiomyomas, Associated with a High Estrogenic Environment and Unrelated to Proliferative Activity"J. Clin. Endocrinol. Metab.. 87. 1729-1736 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ayaka Orii, Hiroshi Masutani, Toshio Nikaido, Ya-Li Zhai, Kiyoshi Kato, Masatoshi Kariya, Ikuo Konishi, Junji Yodoi, and Shingo Fujii: "Altered Post-Translational Modification of Redox Factor 1 Protein in Human Uterine Smooth Muscle Tumors"J. Clin. Endocrinol. Metab.. 87. 3754-3759 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hiroaki Shime, Masatoshi Kariya, Ayaka Orii, Chika Momma, Takanobu Kanamori, Ken Fukuhara, Takashi Kusakari, Yuko Tsuruta, Kenji Takakura, Toshio Nikaido, and Shingo Fujii: "Tranilast Inhibits the Proliferation of Uterine Leiomyoma Cells in Vitro through G1 Arrest Associated with the Induction of p21(waf1) and p53"J. Clin. Endocrinol. Metab.. 87. 5610-5617 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takanobu Kanamori, Kenji Takakura, Masaki Mandai, Masatoshi Kariya, Ken Fukuhara, Takashi Kusakari, Chika Momma, Hiroaki Shime, Haruhiko Yagi, Mitsunaga Konishi, Ayako Suzuki, Noriomi Matsumura, Kanako Nanbu, Jun Fujita, and Shingo Fujii: "PEP-19 overexpression in human uterine leiomyoma"Mol. Hum. Reprod.. in press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fukuhara K, Kariya M, Monma C, Konishi M, Takakura K, Fujita J, Fujii S: "Beta-caterin overexpression in human uterine leiomyosaroomas"Int J Gynecol Pathol. submitted for publication.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kusakari T, Kariya M, Mandai M, Tsuruta Y, Hamid AA, Fukuhara K, Nanbu K, Takakura K, Fujii S.: "C-erbB-2 ornaurar Ha-ras iduced malignant transformation ogf immortalized human obarian surface epithelial cells in vivo"Eur J Cancer. in press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kido A, Monma C, Togashi K, Ueda H, Itoh K, Fujii S, Konishi J.: "Uterine arterial embolization for the treatment of diffuse leiomyomatosis A case report"J Vasc Interv Radiol.. In press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakai A, Togashi K, Ueda H, Koyama T, Yamaoka T, Fujii S, Konishi J.: "The junctional zone on MR imaging continuous change on ultra fast images"Journal of Woman's Imaging. 3. 89-93 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tanri Shiozawa, Akiko Horiuchi, Kiyoshi Kato, Miyuki Obinata, Ikuo Konishi, Shingo Fujii, and Toshio Nikaido: "Up-Regulation of p27Kip1 by Progestins Is Involved in the Growth Suppression of the Normal and Malignant Human Endometrial Glandular Cells"Endocrinology. 142. 4182-4188 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shinozawa T, Itoh K, Horiuchi A, Konishi I, Fujii S, Nikaido T.: "Down-regulation of estrogen receptor by themethylation of the estrogen receptor gene in endometrial carcinoma"Anticancer Res.. 22. 139-143 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Higashitsuji Hisako, Higashitsuji H, Nagao T, Nonoguchi K, Fujii S, Itoh K, Fujita J.: "A novel protein expressed in hepatoma accelerates export of NF-κβ from the nucleus and inhibits p53-dependent apoptosis"Cancer Cell. 2. 33-346 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Atia A. Hamid, Masaki Mandai, Ikuo Konishi, Kanako Nanbu, Yuko Tsuruta, Takashi Kusakari, Masatoshi Kariya, Masato Kita, Shingo Fujii: "Cyclical change of hMSH2 protein expression in normal endometrium during the menstrual cycle and its overexpression in endometrial hyperplasia and sporadic endometrial carcinoma"Cancer. 94. 997-1005 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] KATAOKA, M., TOGASHI, K., YAMAOKA, T., NAKAI, A., UEDA, H., FUJII, S., KONISHI, J.: "Benign Conditions Simulating Gynecologic Malignancies on MR Imaging"The Radiogist. 8. 163-173 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kataoka M, Togashi K. Yamaoka T, Iwasa Y, Fujii, S., Konishi, J.: "MR Imaging of Mullerian Mucinous Bordeline Tumors Arising From Endometriotic Cysts"J Comput Assist Tomogr. 26. 532-537 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Chie Kuragaki, Takayuki Enomoto, Yuko Ueno, Hongbo Sun, Masami Fujita, Ryuichi Nakashima, Yutaka Ueda, Hiroko Wada, Yuji Murata, Toshihiko Toki, Ikuo Konishi, Shingo Fujii: "Mutations in the STK11 Gene Characterize Minimal Deviation Adenocarcinoma of the Uterine Cervix"Lab Invest. 83. 35-45 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fukuhara K, et al.: "Secreted frizzled related protein 1 is overexpressed in uterine leiomyomas, associated with a high estrogenic environment and unrelated to proliferative activity"J Clin Endocrinol Metab. 87. 1729-1736 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shime H, et al.: "Tranilast Inhibits the Proliferation of Uterine Leiomyoma Cells in Vitro through G1 Arrest Associated with the Induction of p21(wafl) and p53"J Clin Endocrinol Metab. 87. 5610-5617 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Orii A: "Altered post-translational modification of redox factor 1 protein in human uterine smooth muscle tumors"J Clin Endocrinol Metab. 87. 3754-3759 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hamid AA: "Cyclical change of hMSH2 protein expression in normal endometrium during the menstrual cycle and its overexpression in endometrial hyperplasia and sporadic endometrial carcinoma"Cancer. 94. 997-1005 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Higashitsuji Hisako, et al.: "A novel protein expressed in hepatoma accelerates export of NF-kB from the nucleus and inhibits p53-dependent apoptosis"Cancer Cell. 2. 532-537 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kuragaki C: "Mutations in the STK11 Gene Characterize Minimal Deviation Adenocarcinoma of the Uterine Cervix"Lab Invest. 83. 35-45 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Fukuhara, K. et al.: "Secreted frizzled related protein 1 is over-expressed in uterine leiomyoas associated with a high estrogenic environment and is unrelated to proliferative activity"J Clin Endocr Met. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Tsuruta, Y. et al.: "Combination effect of adenovirus-mediated pro-apoptotic bax gene transfer with cisplatin or pacritaxel treatment in ovarian cancer cell lines"Eur J Cancer. 37. 531-541 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kuroda, H. et al.: "Human ovarian surface epithelium (OSE) cells express LH/HCG receptors, and HCG inhibits apoptosis of OSE cells via up-regulation of insulin-like growth factor-1"Int J Cancer. 92. 309-315 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nakayama, K. et al.: "Demonstration of focal p53 expression without genetic alterations in endometriotic lesions"Int J Gynecol Pathol. 20. 227-231 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shiozawa, T. et al.: "Up-regulation of p27Kipl by progestins is involved in the cells growth suppression of the normal and malignant human endometrial glandular cells"Endocrinology. 142. 4182-4188 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shiozawa, T. et al.: "Expression of the cell cycle regulator p27kip1 in normal squamous epithelium, cervical intraepithelial neoplasia, and invasive squamous cell carcinoma of the uterine cervix. Immunohistochemistry and functional aspects of p27kip1"Cancer. 92. 3005-3011 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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