婦人科悪性腫瘍に対する新規治療法の開発：子宮間葉系腫瘍の生物学的応答性の解析

• Project/Area Number: 15K10709
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Shinshu University
• Principal Investigator: 林 琢磨 信州大学, 医学部, 特任教授 (60359726)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Discontinued (Fiscal Year 2016)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: LMP2 / 子宮平滑筋肉腫 / 子宮筋腫 / 子宮間葉系腫瘍 / バイオマーカー / 子宮平滑筋種 / 標的因子

Outline of Annual Research Achievements

子宮平滑筋腫(子宮筋腫)は、50歳以上の成人女性に罹患率70～80％で発症する良性腫瘍で、女性に発生する腫瘍で最も頻度の高い腫瘍のうちの一つである。従来はその大きさを基準に手術が行われてきたが、女性の晩婚化・高齢初産婦の増加などライフスタイルの変化により、40 歳代女性の妊孕性温存希望が強くなっている。故に、今日の子宮筋腫の治療方針ではこの社会的背景を考慮して、子宮を温存する方法が要求される。しかし、子宮筋腫に類似した悪性疾患である子宮肉腫がまれながら存在するため、多くの子宮筋腫患者の中で子宮温存の是非を決定する際、その除外診断が重要となる。残念ながら、現行の鑑別法は、手術摘出組織の外科病理診断であり客観性に欠けている。さらに、これまでに各国において臨床試験が行われているが、既存の抗癌剤では、子宮肉腫に対する顕著な延命効果が認められていない。そこで、子宮肉腫に対する新規治療法・診断法の確立に向け、子宮肉腫の生物学的特性を理解することが重要である。
林らの研究グループは、蛋白分解酵素複合体プロテアソームの構成因子であるLMP2の欠損マウスにおいて、子宮肉腫が自然発症することを見出した(利根川 進 教授:米国マサチューセッツ工科大学の研究協力)。そこで、私達は、病理ファイルより選別された各種子宮間葉系腫瘍の生検組織でのLMP2の発現状況について免疫組織化学染色により検討し、特異的に子宮肉腫でLMP2の発現が著しく減弱することを報告した。提携の医療機関との連携の基、私達は、LMP2に着目したDNA MicroArrayの遺伝子プロファイリングを行い、子宮間葉系腫瘍の診断マーカーの候補分子の探索を行っている。本研究より、林らの研究グループは、カベオリン、LMP2、Cyclin Eなどの候補因子に対する子宮間葉系腫瘍の診断マーカーとしての可能性を検討した。

Research Products

• [Int'l Joint Research] Sigma-Aldrich社(Israel)
• [Journal Article] Characterization of leiomyomatoid angiomatous neuroendocrine tumour (LANT)-like tumour in the myometrium with histopathological examination. (2017)
  • Author(s): Hayashi T, Ichimura T, Kasai M, Sano K, Zharhary D, Shiozawa T, Yaegashi N, Konishi I.
  • Journal Title: Anticancer Research Volume: 39(10) Pages: 5127-5138
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Molecular Pathology and Novel Clinical Therapy for Uterine Leiomyosarcoma. (2016)
  • Author(s): Hayashi T, Kawano M, Ichimura T, Ida K, Ando H, Zharhary D, Kanai Y, Aburatani H, Tonegawa S, Shiozawa T, Yaegashi N, Konishi I.
  • Journal Title: Anticancer Research Volume: 38 Pages: 4997-5007
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A Novel Diagnostic Biomarker, PSMB9/b1i, For Human Uterine Leiomyosarcoma. (2016)
  • Author(s): Hayashi T, Kawano M, Ichimura T, Zharhary D, Kanai Y, Tonegawa S, Shiozawa T, Yaegashi N, Konishi I.
  • Journal Title: EC Gynaecology Volume: 01 Pages: 5-6
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Gene analysis of Interferon-g signal molecules in human uterine leiomyosarcoma. (2016)
  • Author(s): Hayashi T, Kawano M, Ichimura T, Kasai M, Ida K, Ando H, Shiozawa T, Tonegawa S, Kanai Y, Aburatani H, Yaegashi N, Konishi I.
  • Journal Title: WULFENIA Journal Volume: 23(9) Pages: 1-18
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genomic Analysis of Sarcomagenesis (2016)
  • Author(s): Hayashi T, Horiuchi A, Kanai Y, Yaegashi N, Shiozawa T, Tonegawa S, Konishi I.
  • Journal Title: Journal of Gynecology and Obstetrics Bulletin Volume: 1(1) Pages: 1-2
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Uterine Leiomyosarcoma Tumorigenesis in Lmp2-deficient Mice: Involvement of Impaired Anti-oncogenic Factor IRF1 (2015)
  • Author(s): Hayashi T, Horiuchi A, Sano K, Yaegashi N, Konishi I
  • Journal Title: Anticancer Research Volume: 35(9) Pages: 4665-4679
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Expression of CAVEOLIN 1 in uterine mesenchymal tumors: no relationship between malignancy and CAVEOLIN 1 expression (2015)
  • Author(s): Hayashi T, Ichimura T, Yaegashi N, Shiozawa T, Konishi I
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 15 Issue: 4 Pages: 1-12
  • DOI: 10.1016/j.bbrc.2015.06.046
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Differential expressions of CAVEOLIN 1 in human uterine mesenchymal tumors and normal myometrium (2015)
  • Author(s): Hayashi T, Horiuchi A, Sano K, Hiraoka N, Ichimura T, Ishiko O, Kanai Y, Yaegashi N, Shiozawa T, Tonegawa S, Aburatani H, Konishi I
  • Journal Title: Jokull Journal Volume: 65(7) Pages: 1-15
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Potential roles of PSMB9/b1i and CAVEOLIN 1 define new targets for uterine leiomyosarcoma therapy. Clinical Application of Protein (2017)
  • Author(s): Kawano M, Hayashi T, Shiozawa T, Ichimura T, Yaegashi N, Tonegawa S, Konishi I
  • Organizer: 10th Anniversary of Protein & Peptide Conference
  • Place of Presentation: Fukuoka, Japan
  • Year and Date: 2017-03-23
  • Int'l Joint Research / Invited
• [Presentation] Potential roles of LMP2/b1i as negative regulator defines new targets for uterine leiomyosarcoma therapy (2016)
  • Author(s): Hayashi T, Kawano M, Sano K, Ichimura T, Kasai M, Kanai Y, Aburatani H, Tonegawa S, Shiozawa T, Yaegashi N, Konishi I
  • Organizer: 2016 International Conference on Biotechnology and Bioengineering (ICBB).
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2016-12-08
  • Int'l Joint Research / Invited
• [Presentation] Uterine Leiomyosarcoma Tumorigenesis in Lmp2-deficient Mice: Involvement of Impaired Anti-oncogenic Factor IRF1. (2016)
  • Author(s): Hayashi T, Horiuchi A, Sano K, Yaegashi N, Konishi I.
  • Organizer: The 75th Annual Meeting of the Japanese Cancer Association. October 8, 2016.
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 2016-10-07
  • Int'l Joint Research / Invited
• [Presentation] Potential roles of PSMB9/b1i and Caveolin 1 define new targets for uterine leiomyosarcoma (2016)
  • Author(s): Hayashi T, Horiuchi A, Shiozawa T, Ishiko O, Yaegashi N, Tonegawa S, Konishi I
  • Organizer: 57thJSCC/ICC2016,
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 2016-05-29
  • Int'l Joint Research / Invited
• [Presentation] Molecular approach of the sarcomagenesis of uterine mesenchymal tumours. (2016)
  • Author(s): Hayashi T, Kanai Y, Kawano M, Osawa S, Aburatani H, Tonegawa S, Yaegashi N, Konishi I.
  • Organizer: World Congress of Cancer Research-2016.
  • Place of Presentation: Shanghai, China
  • Year and Date: 2016-05-13
  • Int'l Joint Research / Invited
• [Presentation] The ICOS-ligand B7-H2, expressed on human type II alveolar epithelial cells, plays a role in the pulmonary host defense system (2016)
  • Author(s): Qian X, Freeman GJ, Tagawa Y-I, Hayashi T
  • Organizer: The Fifth Bizan Immunology Symposium at University of Tokushima. Immunology Program at the University of Tokushima (IPUT)
  • Place of Presentation: Tokushima University School of Medicine, Tokushima, Japan
  • Year and Date: 2016-03-03
  • Int'l Joint Research
• [Presentation] Regenerative effect of Calcineurin inhibitor, Tacrolimus on Optic neuropathy (2015)
  • Author(s): Hayashi T, Nakamura-Yanagidaira T, Hirano T, Murata T
  • Organizer: World Congress of Regenerative Medicine & Stem Cell-2015
  • Place of Presentation: Shanghai, China
  • Year and Date: 2015-11-18
  • Int'l Joint Research / Invited
• [Book] Precision Medicine in Gynecology and Obstetrics (2017)
  • Author(s): Hayashi T*, Sano K, Ichimura T, Kawano M, Kanai Y, Shiozawa T, Yaegashi N, Konishi, I.
  • Publisher: Springer
• [Remarks] 癌抑制因子LMP2 とCalponin h1 とのコミュニケーションリンク
  • URL: http://www.shinshu-u.ac.jp/graduate/medicine/i-topics/#66415