Development of novel cancer therapy by functional up-regulation of dystroglycan using glycosyltransferase LARGE

• Project/Area Number: 24501357
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Clinical oncology
• Research Institution: Teikyo University
• Principal Investigator: SHIMIZU Teruo 帝京大学, 医療技術学部, 教授 (00107666)
• Co-Investigator(Renkei-kenkyūsha): MATSUMURA Kiichiro 帝京大学, 医学部, 教授 (50260922) ; SAITO Fumiaki 帝京大学, 医学部, 准教授 (40286993)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 癌 / 糖鎖 / ジストログリカン / ラミニン / LARGE

Outline of Final Research Achievements

It has been demonstrated that laminin binding activity of α-dystroglycan (α-DG) is reduced in many cancer cells by the defective glycosylation of α-DG and glycosyltransferase LARGE hyperglycosylates and increases its laminin binding activity. In this study, we investigated possible therapeutic strategy for cancer using LARGE. We demonstrated that, in addition to the increment of laminin binding activity, LARGE suppresses proliferation and invasion of cancer cells by modulating gene expression pattern involved in them. However, overexpression of LARGE inhibited differentiation of non-cancer cells, such as myoblasts. Therefore, further experiments are necessary to apply LARGE for the cancer therapy.

Research Products

• [Journal Article] Overexpression of LARGE suppresses muscle regeneration via down-regulation of insulin-like growth factor 1 and aggravates muscular dystrophy in mice. (2014)
  • Author(s): Saito F, Kanagawa M, Ikeda M, Hagiwara H, Masaki T, Ohkuma H, Katanosaka Y, Shimizu T, Sonoo M, Toda T, Matsumura K.
  • Journal Title: Hum Mol Genet Volume: 23 Issue: 17 Pages: 4543-4558
  • DOI: 10.1093/hmg/ddu168
  • Peer Reviewed / Open Access
• [Journal Article] Overexpression of LARGE suppresses muscle regeneration via down-regulation of insulin-like growth factor 1 and aggravates muscular dystrophy in mice (2014)
  • Author(s): Saito F, Kanagawa M, Ikeda M, Hagiwara H, Masaki T, Ohkuma H, Shimizu T, Sonoo M, Toda T, Matsumura K.
  • Journal Title: Hum Mol Genet Volume: in press
  • Peer Reviewed
• [Presentation] LARGEの過剰発現はIGF-1の発現低下により筋再生を抑制してマウスの筋ジストロフィーを悪化させる (2014)
  • Author(s): 斉藤史明、金川基、池田美樹、萩原宏毅、真先敏弘、大熊秀彦、片野坂友紀、清水輝夫、園生雅弘、戸田達史、松村 喜一郎
  • Organizer: 第８７回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-18
• [Presentation] LARGEの過剰発現による筋ジストロフィーモデルマウスにおける筋再生の抑制 (2014)
  • Author(s): 斉藤史明、金川基、池田美樹、萩原宏毅、真先敏弘、大熊秀彦、片野坂友紀、清水輝夫、園生雅弘、戸田達史、松村 喜一郎
  • Organizer: 第３７回日本神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-11
• [Presentation] FukutinノックアウトマウスにおけるLARGEの過剰発現 - 治療応用へ向けての課題 - (2014)
  • Author(s): 斉藤史明、金川基、萩原宏毅、真先敏弘、池田美樹、清水輝夫、園生雅弘、戸田達史、松村 喜一郎
  • Organizer: 第５５回日本神経学会学術大会
  • Place of Presentation: 福岡
  • Year and Date: 2014-05-24
• [Presentation] 骨格筋特異的Fukutin欠損マウスに対するLARGEの過剰発現の影響
  • Author(s): 斉藤史明，金川基，萩原宏毅，真先敏弘，池田美樹，清水輝夫，園生雅弘，戸田達史，松村喜一郎
  • Organizer: 第５４回日本神経学会学術大会
  • Place of Presentation: 東京
• [Presentation] レスベラトロールの先天性筋ジストロフィーモデルマウス対する効果の検討
  • Author(s): 萩原宏毅，斉藤史明，真先敏弘，清水輝夫，松村喜一郎，園生雅弘
  • Organizer: 第５４回日本神経学会学術大会
  • Place of Presentation: 東京
• [Presentation] Effects of overexpression of LARGE on a mouse model of congenital muscular dystrophy
  • Author(s): Saito F, Hagiwara H, Ikeda M, Masaki T, Shimizu T, Matsumura K.
  • Organizer: 17th International congress of the World Muscle Society
  • Place of Presentation: Perth, Australia
• [Presentation] The role of the transcriptional factor Pax3 on myogenesis and the effect on the expression of myogenic regulatory factor
  • Author(s): Hagiwara H, Shan H, Masaki T, Ikeda M, Shimizu T, Matsumura K, Saito F.
  • Organizer: 17th International congress of the World Muscle Society
  • Place of Presentation: Perth, Australia
• [Presentation] 転写因子 Pax3は MyoDと細胞周期の制御因子に作用して筋分化を抑制する
  • Author(s): 萩原宏毅，斉藤史明，真先敏弘，清水輝夫，松村喜一郎，園生雅弘
  • Organizer: 第５３回日本神経学会学術大会
  • Place of Presentation: 東京