Inhibition of Notch pathway prevents osteosarcoma growth by cell cycle regulation

• Project/Area Number: 19591725
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Kagoshima University
• Principal Investigator: SETOGUCHI Takao Kagoshima University, 医学部・歯学部附属病院, 助教 (40423727)
• Co-Investigator(Kenkyū-buntansha): ARISHIMA Yoshiya 鹿児島大学, 医学部・歯学部附属病院, 助教 (90336339) ; KOMIYA Setsuro 鹿児島大学, 大学院・医歯学総合研究科, 教授 (30178371)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2008: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2007: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
• Keywords: 骨肉腫 / Notch / 細胞周期 / HEY / osteosarcoma / cell cycle

Research Abstract

骨肉腫患者より採取した腫瘍組織を用いて検討したところ骨肉腫腫瘍組織では10例中10例でNotch2,JAG1が発現上昇していた。ーゲット遺伝子であるHEY1は10例中8例で発現上昇していた。HEY2も10例中9例で上昇していた。次にNotchシグナルを抑制すると骨肉腫細胞株の増殖がin vitro, in vivoにおいて抑制されることが確認された。さらに細胞周期を正に制御するサイクリンD,E, c-Myc, SKP2の発現が抑制され、逆に細胞周期を負に制御するp21Cip1の発現が増大していることを見出した。本研究は、Notchシグナルが骨肉腫の新たな治療的ターゲットとなりうることを示唆している。

Research Products

• [Journal Article] Inhibition of Notch pathway prevents osteosarcoma growth by cell cycle regulation (2009)
  • Author(s): Motoyuki Tanaka, Takao Setoguchi, Masataka Hirotsu, Hui Gao, Hiromi Sasaki, Yukihiro Matsunoshita, Setsuro Komiya
  • Journal Title: British Journal of Cancer 100 Pages: 1957-65
  • Peer Reviewed
• [Journal Article] Stem cell factor prevents neuronal cell apoptosis after acute spinal cord injury. (2009)
  • Author(s): Yamasaki K, Setoguchi T, Takenouchi T, Yone K, Komiya S
  • Journal Title: Spine. 15;34(4) Pages: 323-7
  • NAID: 10027238493
  • Peer Reviewed
• [Journal Article] Aging-related loss of the chromatin protein HMGB2 in articular cartilage is linked to reduced cellularity and osteoarthritis. (2009)
  • Author(s): Taniguchi N, Carames B, Ronfani L, Ulmer U, Komiya S, Bianchi ME, Lotz M
  • Journal Title: Proc Natl Acad Sci USA 27;(106)4 Pages: 1181-6
  • Peer Reviewed
• [Journal Article] Activation of synoviolin promoter in rheumatoid synovial cells by a novel transcription complex of interleukin enhancer binding factor 3 and GA binding protein alpha. (2009)
  • Author(s): Izumi T, Fujii R, Izumi T, Nakazawa M, Yagishita N, Tsuchimochi K, Yamano Y, Sato T, Fujita H, Aratani S, Araya N, Azakami K, Hasegawa D, Kasaoka S, Tsuruta R, Yokouti M, Ijiri K, Beppu M, Maruayama I, Nishioka K, Maekawa T, Komiya S, Nakajima T
  • Journal Title: Arthritis Rheum 60(1) Pages: 63-72
  • Peer Reviewed
• [Journal Article] Inhibition of Notch pathway prevents osteosarcoma growth by cell cycle regulation (2009)
  • Author(s): Motoyuki Tanaka
  • Journal Title: British Journal of Cancer in press
  • Peer Reviewed
• [Journal Article] Expression of osterix inhibits bone morphogenetic protein-induced chondrogenic differentiation of mesenchymal progenitor cells. (2008)
  • Author(s): Tominaga H, Maeda S, Miyoshi H, Miyazono K, Komiya S, Imamura T
  • Journal Title: J Bone Miner Metab. 27(1) Pages: 36-45
  • NAID: 10025336129
  • Peer Reviewed
• [Journal Article] Smurf2 induces ubiquitin-dependent degradation of Smurf1 to prevent migration of breast cancer cells. (2008)
  • Author(s): Fukunaga E, Inoue Y, Komiya S, Horiguchi K, Goto K, Saitoh M, Miyazawa K, Koinuma D, Hanyu A, Imamura T
  • Journal Title: J Biol Chem. 19;283(51) Pages: 35660-7
  • Peer Reviewed
• [Journal Article] CAAT/enhancer-binding protein beta promotes osteoblast differentiation by enhancing Runx2 activity with ATF4. (2008)
  • Author(s): Tominaga H, Maeda S, Hayashi M, Takeda S, Akira S, Komiya S, Nakamura T, Akiyama H, Imamura T
  • Journal Title: Mol Biol Cell. 19(12) Pages: 5373-86
  • Peer Reviewed
• [Journal Article] Extracellular high mobility group box chromosomal protein 1 is a coupling factor for hypoxia and inflammation in arthritis. (2008)
  • Author(s): Hamada T, Torikai M, Kuwazuru A, Tanaka M, Horai N, Fukuda T, Yamada S, Nagayama S, Hashiguchi K, Sunahara N, Fukuzaki K, Nagata R, Komiya S, Maruyama I, Fukuda T, Abeyama K
  • Journal Title: Arthritis Rheum. 58(9) Pages: 2675-85
  • Peer Reviewed
• [Journal Article] Differential expression of GADD45beta in normal and osteoarthritic cartilage: potential role in homeostasis of articular chondrocytes. (2008)
  • Author(s): Uhuru Jm Zerbini LF, Peng H, Otu HH, Tsuchimochi K, Otero M, Dragomir C, Walsh N, Bierbaum BE, Mattingly D, van Flandern G, Komiya S, Aigner T, Libermann TA, Goldring MB
  • Journal Title: Arthritis Rheum. 58(7) Pages: 2075-87
  • Peer Reviewed
• [Journal Article] Expression of apoptosis signal-regulating kinase 1 in mouse spinal cord under chronic mechanical compression: possible involvement of the stress-activated mitogen-activated protein kinase pathways in spinal cord cell apoptosis. (2008)
  • Author(s): Takenouchi T, Setoguchi T, Yone K, Komiya S.
  • Journal Title: Soine 15;33(18) Pages: 1943-50
  • Peer Reviewed
• [Journal Article] Stage-specific secretion of HMGB1 in cartilage regulates endochondral ossification. (2007)
  • Author(s): Taniguchi N, Yoshida K, Ito T, Tsuda M, Mishima Y, Furumatsu T, Ronfani L, Abeyama K, Kawahara K, Komiya S, Maruyama I, Lotz M, Bianchi ME, Asahara H.
  • Journal Title: Mol Cell Biol. 27(16) Pages: 5650-63
  • Peer Reviewed
• [Presentation] Notchシグナルを標的とした骨肉腫に対する治療 (2008)
  • Author(s): 瀬戸口啓夫
  • Organizer: 第41回日本整形外科・骨軟部腫瘍学術集会シンポディウム
  • Place of Presentation: アクトシティ浜松(浜松市)
  • Year and Date: 2008-07-18
• [Presentation] (シンポディウム)Notchシグナルを標的とした骨肉腫に対する治療 (2008)
  • Author(s): 瀬戸口啓夫、田中源幸、廣津匡隆、佐々木裕美、小宮節郎
  • Organizer: 第41回日本整形外科骨・軟部腫瘍学術集会
  • Place of Presentation: 京都交際会館
• [Presentation] Notch pathway is activated in osteosarcoma and inhibition of γ-secretase inhibit osteosarcoma growth by cell cycle regulation (2008)
  • Author(s): Tanaka M. Setoguchi T. Hirotsu M. Sasaki H. Komiya S.
  • Organizer: The 30st Annual Meeting of the American Society for Bone and Mineral Research
  • Place of Presentation: モントリオールカナダ
• [Presentation] New investigator recognition award 受賞 Notch pathway is activated in osteosarcoma and inhibitors of γ-secretase prevents osteosarcoma growth by cell cycle regulation (2008)
  • Author(s): Takao Setoguchi, Motoyuki Tanaka, Masataka Hirotsu, Hiromi Sasaki, Setsuro Komiya
  • Organizer: Annual meeting of Orthopaedic research Society
  • Place of Presentation: サンフランシスコ
• [Presentation] Notch Pathway is Activated in Osteosarcoma and Inhibitors of γ-secretase Prevents Osteosarcoma Growth by Cell Cycle Regulation (2008)
  • Author(s): 瀬戸口啓夫、小宮節郎
  • Organizer: 54th Annual Meeting of the Orthopaedic Research Society
  • Place of Presentation: San Francisco, California U.S.A.
• [Presentation] 骨肉種におけるNotch の発現と機能v (2007)
  • Author(s): 瀬戸口啓夫、田中源幸、廣津匡隆、佐々木裕美、小宮節郎
  • Organizer: 第30回日本分子生物学会年会
  • Place of Presentation: 横浜市
• [Presentation] 整形外科悪性腫瘍におけるNotchの発現とその意義 (2007)
  • Author(s): 田中源幸、瀬戸口啓夫、小宮節郎
  • Organizer: 第112回西日本整形・災害外科学会
  • Place of Presentation: 日米子
• [Presentation] 骨肉腫におけるNotch の発現とその機能 (2007)
  • Author(s): 田中源幸、瀬戸口啓夫、小宮節郎
  • Organizer: 第22回日本整形外科学会基礎学術集会
  • Place of Presentation: 浜松市
• [Presentation] In vivo inhibition of osteosarcoma growth by Notch pathway inhibition (2007)
  • Author(s): Setoguchi T. Tanaka M. Hirotsu M. Sasaki H. Komiya S.
  • Organizer: 6^<th> Combined Meeting of the Orthopaedic Research Society
  • Place of Presentation: ホノルル ハワイ
• [Presentation] 悪性骨・軟部腫瘍におけるNotch の発現とその意義 (2007)
  • Author(s): Setoguchi T., Tanaka M., Komiya S.
  • Organizer: 第40回日本整形外科骨・軟部腫瘍学術集会
  • Place of Presentation: 甲府市
• [Presentation] Gamma secreatse inhibitor blocks Notch activation and prevented osteosarcoma cells proliferation in vitro and in vivo (2007)
  • Author(s): 瀬戸口啓夫、小宮節郎
  • Organizer: Combined Meeting of the Orthopaedic Research Society
  • Place of Presentation: Honolulu, Hawaii U.S.A.
• [Presentation] In vivo Inhibition of Osteosarcoma Growth by Notch Pathway Inhibition (2007)
  • Author(s): 瀬戸口啓夫、小宮節郎
  • Organizer: The 29th Annual Meeting of the American Society for Bone and Mineral Research
  • Place of Presentation: Honolulu, Hawaii U.S.A.
• [Presentation] 骨肉腫におけるNotchの発現と機能 (2007)
  • Author(s): 瀬戸口啓夫、小宮節郎
  • Organizer: 第30回日本分子生物学会大会
  • Place of Presentation: 横浜 パシフィコ横浜
• [Presentation] In vivo Inhibition of Osteosarcoma Growth by Notch Pathway Inhibition (2007)
  • Author(s): 瀬戸口啓夫、小宮節郎
  • Organizer: 第66回癌学会学術総会
  • Place of Presentation: 横浜 パシフィコ横浜