For development of a new therapeutic approach : Examination of biological response of uterine leiomyosarcoma in microenvironments

• Project/Area Number: 21592126
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Shinshu University
• Principal Investigator: HAYASHI Takuma 信州大学, 医学系研究科, 准教授 (60359726)
• Co-Investigator(Renkei-kenkyūsha): KONISHI Ikuo 京都大学, 大学院・医学系研究科, 教授 (90192062)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2011: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2010: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2009: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: LMP2 / 子宮平滑筋肉腫 / 血行性転移 / 老化 / leiomyosarcoma / angiogenesis / leiomyosarcome / 微小環境 / 血管新生

Research Abstract

Hayashi et al. reported that defective LMP2 expression is likely to be one of the risk factors in the development of human uterine LMS as it is in LMP2-deficient mice. The importance of the IFN-γpathway in the transcriptional regulation of the LMP2 promoter has been established in another study, where defective LMP2 expression was attributable to mutations in the catalytic region of JAK1 in a human uterine LMS SKN cell line.
In the present study, we investigated whether LMP2 expression was markedly down-regulated in human uterine LMS tissues in comparison with both LMA and normal myometrium. Biological and histological findings showed that defective LMP2 expression contributed to abnormal cell proliferation, which directly correlated to tumor progression. Disruption of LMP2 expression stemmed from defects in the IFN-γsignaling pathway, specifically from somatic mutations in JAK1. Furthermore, LMP2 expression appeared to be responsible for the suppression of specific transformed phenotypes of human uterine LMS cells in an anti-oncogenic manner. Continued improvement of our knowledge of the molecular biology of uterine LMS may ultimately lead to novel diagnoses and therapies and improved outcome.

Research Products

• [Journal Article] Tumor Immunoediting from T cell-Mediated Immune Surveillance to Tumor-Escape of Uterine Laiomyosarcoma (2012)
  • Author(s): Hayashi T, Horiuchi A, Sano K, HiraokaN, Ichimura T, Ishiko O, Kanai Y, Yaegashi N, Aburatani H, Shiozawa T, Tonegawa S, Konishi I
  • Journal Title: J Vaccines Vacci Volume: S1 Pages: 1-6
  • Peer Reviewed
• [Journal Article] Potential role of LMP2 astumor-suppressor defines new targets for uterine leiomyosarcoma therapy (2011)
  • Author(s): Hayashi T, Horiuchi A, Sano K, HiraokaN, Kanai Y, Aburatani H, Shizawa T, andKonishi I
  • Journal Title: Scientific Reports
  • Peer Reviewed
• [Journal Article] Tumor immunoediting ; from immunosurveillance to tumor-escape on uterine leiomyosarcma (2011)
  • Author(s): Hayashi T, Horiuchi A, Sano K, HiraokaN, Kasai M, Ichimura T, Nagase S, IshikoO, Kanai Y, Yaegashi N, Aburatani H, Shiozawa T, Tonegawa S, Konishi I
  • Journal Title: Current Res. Cancer Volume: 4 Pages: 36-45
  • Peer Reviewed
• [Journal Article] Involvement of proteasomeβ1i subunit, LMP2, on development of uterine leiomyosarcma (2011)
  • Author(s): Hayashi T, Horiuchi A, Sano K, HiraokaN, Kasai M, Ichimura T, Nagase S, IshikoO, Kanai Y, Yaegashi N, Aburatani H, Shiozawa T, Tonegawa S, Konishi I
  • Journal Title: North Ame J Med Sci Volume: 3 Pages: 394-399
  • Peer Reviewed
• [Journal Article] Involvement of LMP2, IFN-γ-inducible factor, on development of uterine leiomyosarcma (2011)
  • Author(s): Hayashi T, Horiuchi A, Sano K, HiraokaN, Kasai M, Ichimura T, Nagase S, IshikoO, Kanai Y, Yaegashi N, Aburatani H, Shiozawa T, Tonegawa S, Konishi I
  • Journal Title: Current Res. Immunol Volume: 5 Pages: 51-63
  • Peer Reviewed
• [Journal Article] Molecular approach on uterine leiomyosarcoma : LMP2-deficient mice as an animal model of spontaneous uterine leiomyosarcoma (2011)
  • Author(s): Hayashi T, Horiuchi A, Sano K, Hiraoka N, Kanai Y, Shizawa T, Tonegawa S and Konishi I
  • Journal Title: Sarcoma Pages: 1-6
  • Peer Reviewed
• [Journal Article] Hypoxia upregulates ovarian cancer invasiveness via the binding of HIF-1a to a hypoxia-induced, methylation free hypoxia response element(HRE) of S100A4 gene (2011)
  • Author(s): Horiuchi A, Hayashi T, Kikuchi N, Hayashi A, Fuseya C, Shiozawa T andKonishi I
  • Journal Title: Intl. J. Cancer Volume: (in press)
  • Peer Reviewed
• [Journal Article] Potential role of LMP2 as tumor-suppressor defines new targets for uterine leiomyosarcoma therapy (2011)
  • Author(s): Hayashi, T, A.Horiuchi, K.Sano, N.Hiraoka, M.Kasai, T.Ichimura, T.Sudo, Y.Tagawa, R.Nishimura, Ol Ishiko, Y.Kanai, N.Yaegashi, H.Aburatani, T.Shiozawa, I.Konishi
  • Journal Title: Sci Rep Volume: 1 Issue: 1 Pages: 180-180
  • DOI: 10.1038/srep00180
  • Peer Reviewed
• [Journal Article] Involvement of proteasome ss1i subunit, LMP2, on development of uterin leiomyosarcma (2011)
  • Author(s): Hayashi T, Horiuchi A, Sano K, Hiraoka N, Kasai M, Ichimura T, Nagase S, Ishiko O, Kanai Y, Yaegashi N, Aburatani H, Shiozawa T, Tonegawa S, Konishi I
  • Journal Title: North Ame J Med Sci Volume: 3 Pages: 394-399
  • Peer Reviewed
• [Journal Article] Molecular approach on uterine leiomyosarcoma : LMP2-deficient mice as an animal model of spontaneous uterine leiomyosarcoma (2011)
  • Author(s): Hayashi T, Horiuchi A, Sano K, Hiraoka N, Kanai Y, Shizawa T, Tonegawa S, Konishi I
  • Journal Title: Sarcoma Volume: 1 Pages: 1-6
  • Peer Reviewed
• [Journal Article] Molecular approach on uterine leiomyosarcoma : LMP2-deficient mice as an animal model of spontaneous uterine leiomyosarcoma (2010)
  • Author(s): Hayashi T, Horiuchi A, Sano K, HiraokaN, Kanai Y, Shiozawa T, Tonegawa S andKonishi I
  • Journal Title: The Molecular Basis of Sarcoma Pages: 1-6
  • Peer Reviewed
• [Journal Article] Mice-lacking LMP2, proteasome subunit, as an animal model of spontaneous uterine leiomyosarcoma (2010)
  • Author(s): Hayashi T, Horiuchi A, Sano K, Hiraoka N, Kanai Y, Shiozawa T, Tonegawa S and Konishi I
  • Journal Title: Protein and Cell Volume: 1 Pages: 711-717
  • Peer Reviewed
• [Journal Article] Mice-lacking LMP2, IFN-γ-inducible factor, as an Animal Model of Spontaneous Uterine Leiomyosarcoma (2010)
  • Author(s): Hayashi T, Horiuchi A, Sano K, Hiraoka N, Kanai Y, Aburatani H, Shiozawa T, Tonegawa S and Konishi I
  • Journal Title: Current Res. Immunol Volume: 4 Pages: 1-12
  • Peer Reviewed
• [Journal Article] Mice-lacking LMP2, IFN-γ-inducible factor, as an Animal Model of Spontaneous Uterine Leiomyosarcoma (2010)
  • Author(s): Hayashi T, Horiuchi A, Sano K, Hiraoka N, Kanai Y, Aburatani H, Shiozawa T, Tonegawa S, Konishi I
  • Journal Title: Curren t Res.Immunol Volume: 4 Pages: 1-12
  • Peer Reviewed
• [Journal Article] Potentiation of TLR9 responses for human naive B-cell growth through RP105 signaling (2010)
  • Author(s): Kazuko Yamazaki
  • Journal Title: Clinical Immunology 135 Pages: 125-136
  • Peer Reviewed
• [Journal Article] Type-specific roles of histone deacetylase(HDAC)overexpression in ovarian carcinoma : HDACl enhances cell proliferation and HDAC3 stimulates cell migration with down-regulation of E-cadherin. (2010)
  • Author(s): Akiko Hayashi
  • Journal Title: International J. Cancer 126 Pages: 1-15
  • Peer Reviewed
• [Journal Article] Tumor immunoediting : from immunosurveillance to tumor escape-incase of uterine leiomyosarcoma-. (2009)
  • Author(s): Takuma Hayashi
  • Journal Title: Current Research Immunology 1 Pages: 33-46
  • Peer Reviewed
• [Journal Article] Priorityの重要性:ヒト子宮平滑筋肉腫のバイオマーカーの発見と新規診断法の確立 (2009)
  • Author(s): 林琢磨
  • Journal Title: 癌と人 36 Pages: 57-58
  • NAID: 120005223284
  • Peer Reviewed
• [Presentation] Molecular mechanism of hematogenous (2012)
  • Author(s): Konishi I
  • Organizer: シンポジウムWorld Cancer Meeting
  • Place of Presentation: China
• [Presentation] 子宮平滑筋肉腫の生物学的応答性:ベンチワークからベッドサイトへ子宮筋層内膜症(特別講演) (2011)
  • Author(s): 林琢磨
  • Organizer: 第51回婦人科腫瘍学会
  • Place of Presentation: 福岡
  • Year and Date: 2011-11-25
• [Presentation] Potential role of LMP2 as tumor-suppressor defines new targets for uterine leiomyosarcoma therapy (2011)
  • Author(s): Hayashi T, Horiuchi A, Shiozawa T, Tonegawa S, Konishi I
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(招待講演)
  • Year and Date: 2011-10-03
• [Presentation] LMP2-Deficient mice as animal model of spontaneous uterine leiomyosarcoma for Development of Diagnosis and Anti-tumor Drug (2011)
  • Author(s): Hayashi T, Horiuchi A, Shiozawa T, Tonegawa S, Konishi I
  • Organizer: シンポジウムWorld BiologicalMeeting
  • Place of Presentation: China
• [Presentation] Molecular mechanism on uterine leiomyosarcoma tumori genesis : LMP2 and Cell Clock Connection (2010)
  • Author(s): 林琢磨
  • Organizer: 京都大学婦人科腫瘍学セミナー・京都大学がんプロフェショナル養成プラン
  • Place of Presentation: 京都
  • Year and Date: 2010-06-07
• [Presentation] 子宮平滑筋肉腫の細胞浸潤と血行性転移について:サイトカインとLMP2の関連性、シンポジウム:婦人科がん治療標的探索の最前線 (2010)
  • Author(s): 林琢磨、堀内晶子、油谷浩幸、塩沢丹里、利根川進、小西郁生
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
• [Presentation] Establish ment of diagnostic biomarker against uterine leiomyosarcoma for Development of Diagnosis and Anti-tumor Drug (2010)
  • Author(s): Hayashi T, Horiuchi A, Aburatani H, Shiozawa T, Tonegawa S and Konishi I
  • Organizer: International Cancer Meeting 2010
  • Place of Presentation: Singapore
• [Presentation] シンポジウム:婦人科がん治療標的探索の最前線:子宮平滑筋肉腫の細胞浸潤と血行性転移について:サイトカインとLMP2の関連性 (2010)
  • Author(s): 林琢磨、堀内晶子、油谷浩幸、塩沢丹里、利根川進、小西郁生
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪国際会議場(招待講演)
• [Presentation] LMP2とCyclin Eをバイオマーカーとした子宮平滑筋肉腫に対する新規診断法 (2009)
  • Author(s): Takuma Hayashi
  • Organizer: 一般口演、創薬イノベーションフォーラム2009
  • Place of Presentation: 東京、日本
  • Year and Date: 2009-12-15
• [Presentation] 子宮平滑筋肉腫の発症機序の解析と新規バイオマーカーを用いた診断法の確立 (2009)
  • Author(s): 林琢磨
  • Organizer: 東北大学病院がんセミナー・東北がんプロフェショナル養成プラン
  • Place of Presentation: 仙台
  • Year and Date: 2009-07-16
• [Presentation] 子宮平滑筋肉腫の発症機序の解析と新規バイオマーカーを用いた診断法の確立 (2009)
  • Author(s): Takuma Hayashi
  • Organizer: 東北大学病院がんセミナー・東北がんプロフェショナル養成プラン、依頼講演
  • Place of Presentation: 仙台、日本
  • Year and Date: 2009-07-16
• [Presentation] 子宮平滑筋肉腫の血行性転移の分子生物学的解析: LMP2の発現の関与について (2009)
  • Author(s): 林琢磨、堀内晶子、小西郁生
  • Organizer: がん転移治療の最前線~臨床・創薬~、第18回日本がん転移学会学術集会総会
  • Place of Presentation: 旭川
• [Presentation] LMP2-Deficient Mice as Animal Model of Spontaneous Uterine (2009)
  • Author(s): Takuma Hayashi
  • Organizer: Leiomyosarcoma for Development of Diagnosis and Anti-tumor Drug World Cancer Congress 2009
  • Place of Presentation: Beijing, China
• [Presentation] LMP2-Deficient Mice as Animal Model of Spontaneous Uterine Leiomyosarcoma for Development of Diagnosis and Anti-tumor Drug (2009)
  • Author(s): Takuma Hayashi
  • Organizer: シンポジウムWorld Cancer Congress 2009国際会議、招待講演
  • Place of Presentation: Beijing, China
• [Presentation] Established LMP2-Biomarker for Development of Diagnosis and Anti-tumor Drug against Uterine Leiomyosarcoma. (2009)
  • Author(s): Takuma Hayashi
  • Organizer: シンポジウム2nd Annual Congress and Expo of Molecular Diagnostics(CEMD-2009)、国際会議招待講演
  • Place of Presentation: Beijing, China
• [Presentation] A novel diagnostic biomaker, LMP2, for human uterine leiomyosarcoma. (2009)
  • Author(s): Takuma Hayashi
  • Organizer: 一般口演、The 20th Asia Pacific Cancer Conference、国際会議
  • Place of Presentation: Tsukuba, Japan
• [Presentation] 子宮平滑筋肉腫の血行性転移の分子生物学的解析:LMP2の発現の関与について (2009)
  • Author(s): Takuma Hayashi
  • Organizer: シンポジウム、第18回日本がん転移学会学術集会総会、依頼講演
  • Place of Presentation: 旭川、日本
• [Presentation] Detection of somatic mutation on IFN-γ signaling pathway in Uterine Leiomyosarcoma (2009)
  • Author(s): Kano H, Horiuchi A, Konishi I, Hayashi T
  • Organizer: 第68回日本癌学会(Workshop)
  • Place of Presentation: 横浜、日本
• [Presentation] Established LMP2-Biomarker for Development of Diagnosis and Anti-tumor Drug against Uterine Leiomyosarcoma. (2009)
  • Author(s): Takuma Hayashi
  • Organizer: 第68回日本癌学会(Workshop)
  • Place of Presentation: 横浜、日本
• [Remarks]
  • URL: http://www.shinshu-u.ac.jp/faculty/medicine/department/doctor/zouki/immunol/main_frame.htm
• [Remarks]
  • URL: http://www.shinshu-u.ac.jp/good_practice/cancer_gp/course/course04/
• [Patent(Industrial Property Rights)] LMP2 for use as a marker in detecting uterine leiomyosarcoma (2008)
  • Inventor(s): 林琢磨、堀内晶子、小林幸弘、佐野健司、小西郁生
  • Industrial Property Rights Holder: 国立大学法人,信州大学
  • Filing Date: 2008-06-24
  • Acquisition Date: 2011-08-24
  • Overseas
• [Patent(Industrial Property Rights)] Detection of uterine leiomyosarcoma using LMP2 (2008)
  • Inventor(s): 林琢磨、堀内晶子、小林幸弘、佐野健司、小西郁生
  • Industrial Property Rights Holder: 国立大学法人,信州大学
  • Filing Date: 2008-05-30
  • Acquisition Date: 2012-03-02
  • Overseas
• [Patent(Industrial Property Rights)] ヒト子宮平滑筋肉腫の新規鑑別マーカー:イムノプロテアソームLMP2 (2005)
  • Inventor(s): 林琢磨
  • Industrial Property Rights Holder: 国立大学法人,信州大学
  • Filing Date: 2005-11-30
  • Overseas
• [Patent(Industrial Property Rights)] LMP2を用いた子宮平滑筋肉腫の検出 (2005)
  • Inventor(s): 林琢磨、堀内晶子、小林幸弘、佐野健司、小西郁生
  • Industrial Property Rights Holder: 国立大学法人,信州大学
  • Industrial Property Number: 2007-548042
  • Filing Date: 2005-11-30
  • Acquisition Date: 2012-04-03
• [Patent(Industrial Property Rights)] ヒト子宮平滑筋肉腫の新規鑑別マーカー:イムノプロテアソームLMP2 (2005)
  • Inventor(s): 林琢磨、小林幸弘、佐野健司、堀内晶子、小西郁生
  • Industrial Property Rights Holder: 国立大学法人信州大学
  • Filing Date: 2005-11-30
• [Patent(Industrial Property Rights)] ヒト子宮平滑筋肉腫の新規鑑別マーカー:イムノプロテアソームLMP2 (2005)
  • Inventor(s): 林琢磨、小林幸弘、佐野健司、堀内晶子、小西郁生
  • Industrial Property Rights Holder: 国立大学法人信州大学
  • Filing Date: 2005-11-30
  • Overseas
• [Patent(Industrial Property Rights)] ヒト子宮平滑筋肉腫の新規鑑別マーカー:イムノプロテアソームLMP2 (2005)
  • Inventor(s): 林琢磨、小林幸弘、佐野健司、堀内晶子、小西郁生
  • Industrial Property Rights Holder: 国立大学法人信州大学
  • Filing Date: 2005-11-30
  • Acquisition Date: 2011-08-24
  • Overseas