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2002 Fiscal Year Final Research Report Summary

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)
Project Period (FY) 2001 – 2002
KeywordsUterus / leiomyoma / Ref-1 / mast cell / p53 / sFRP-1 / pathogenesis / treatment
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

  • Research Products

    (21 results)

All Other

All Publications (21 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)

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  • [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)

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  • [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)

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  • [Publications] Takanobu Kanamori, et al.: "PEP-19 overexpression in human uterine leiomyoma"Mol Hum Reprod. (in press).

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  • [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).

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  • [Publications] Akiko Kido, et al.: "Uterine arterial embolization for the treatment of diffuse leiomyomatosis. A case report"J Vasc Interv Radiol. (in press).

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  • [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)

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  • [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)

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  • [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)

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  • [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.

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  • [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.

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  • [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.

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  • [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.

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  • [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)

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  • [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)

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  • [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)

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  • [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)

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  • [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)

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  • [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)

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  • [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)

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  • [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)

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Published: 2004-04-14  

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