Establishment of osteosarcoma stem cell model induced by RAGE and elucidation of its molecular mechanism

• Project/Area Number: 15K10435
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Kanazawa University
• Principal Investigator: Takeuchi Akihiko 金沢大学, 医学系, 助教 (70512218)
• Co-Investigator(Kenkyū-buntansha): 山本 靖彦 金沢大学, 医学系, 教授 (20313637)
• Co-Investigator(Renkei-kenkyūsha): MUNESUE Seiichi 金沢大学, 医学系, 助教 (10399040) ; HARASHIMA Ai 金沢大学, 医学系, 助教 (50705522)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• 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: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 骨肉腫 / がん幹細胞 / 幹細胞 / 糖化蛋白受容体

Outline of Final Research Achievements

RAGE (receptor for advanced glycation end-products) overexpressing cells in osteosarcoma (HOS-RAGE)) showed the high cell proliferation and migration ability compared to the control (HOS-mock). HOS-RAGE strongly expressed the stem cell marker (NANOG and SOX2). Microarray analysis of gene expression profiling showed the upregulation of MYC (oncogene). Microarray analysis of miRNA expression profiling showed the downregulation of a certain miRNA. It has been reported that a certain miRNA regulated the expression of pluripotency genes such as SOX2, NANOG and N-MYC in other cancers. Our results suggest the RAGE could suppress the expression of a certain miRNA and may promote the cancer stem-like cell characteristics in osteosarcoma.

Research Products

• [Journal Article] Anti-tumor effects of a nonsteroidal anti-inflammatory drug zaltoprofen on chondrosarcoma via activating peroxisome proliferator-activated receptor gamma and suppressing matrix metalloproteinase-2 expression. (2018)
  • Author(s): Higuchi T, Takeuchi A, Munesue S, Yamamoto N, Hayashi K, Kimura H, Miwa S, Inatani H, Shimozaki S, Kato T, Aoki Y, Abe K, Taniguchi Y, Aiba H, Murakami H, Harashima A, Yamamoto Y, Tsuchiya H.
  • Journal Title: Cancer Med. Volume: 印刷中 Issue: 5 Pages: 1944-1954
  • DOI: 10.1002/cam4.1438
  • NAID: 120006605139
  • Peer Reviewed / Open Access
• [Journal Article] In vitro anticancer effects of a RAGE inhibitor discovered using a structure-based drug design system (2018)
  • Author(s): El-Far Ali、Munesue Seiichi、Harashima Ai、Sato Akira、Shindo Mika、Nakajima Shingo、Inada Mana、Tanaka Mariko、Takeuchi Akihiko、Tsuchiya Hiroyuki、Yamamoto Hiroshi、Shaheen Hazem、El-Sayed Yasser、Kawano Shuhei、Tanuma Sei-Ichi、Yamamoto Yasuhiko
  • Journal Title: Oncology Letters Volume: 15 Pages: 4627-4634
  • DOI: 10.3892/ol.2018.7902
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mid- to long-term clinical outcome of giant cell tumor of bone treated with calcium phosphate cement following thorough curettage and phenolization. (2018)
  • Author(s): Takeuchi A, Suwanpramote P, Yamamoto N, Shirai T, Hayashi K, Kimura H, Miwa S, Higuchi T, Abe K, Tsuchiya H.
  • Journal Title: J Surg Oncol. Volume: 印刷中 Issue: 6 Pages: 1232-1238
  • DOI: 10.1002/jso.24971
  • Peer Reviewed
• [Journal Article] Phase 1/2 study of immunotherapy with dendritic cells pulsed with autologous tumor lysate in patients with refractory bone and soft tissue sarcoma. (2017)
  • Author(s): Miwa S, Nishida H, Tanzawa Y, Takeuchi A, Hayashi K, Yamamoto N, Mizukoshi E, Nakamoto Y, Kaneko S, Tsuchiya H.
  • Journal Title: Cancer Volume: 123 Issue: 9 Pages: 1576-84
  • DOI: 10.1002/cncr.30606
  • Peer Reviewed
• [Journal Article] Pathogenesis of Osteosclerotic Change Following Treatment with an Antibody Against RANKL for Giant Cell Tumour of the Bone. (2017)
  • Author(s): Rosario M, Takeuchi A, Yamamoto N, Hayashi K, Miwa S, Higuchi T, Abe K, Taniguchi Y, Aiba H, Tanzawa Y, Murakami H, Tsuchiya H
  • Journal Title: Anticancer Res. Volume: 32 Pages: 749-54
  • Peer Reviewed
• [Journal Article] Do Mesenchymal Stem Cells Derived From Atypical Lipomatous Tumors Have Greater Differentiation Potency Than Cells From Normal Adipose Tissues? (2017)
  • Author(s): Inatani H, Yamamoto N, Hayashi K, Kimura H, Takeuchi A, Miwa S, Higuchi T, Abe K, Taniguchi Y, Yamada S, Asai K, Otsuka T, Tsuchiya H.
  • Journal Title: Clin Orthop Relat Res Volume: 印刷中 Issue: 6 Pages: 1693-1701
  • DOI: 10.1007/s11999-017-5259-z
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] びまん型腱滑膜巨細胞腫に対するザルトプロフェンの新規薬物療法を目指したパイロットスタディ (2017)
  • Author(s): 武内章彦，山本憲男，林 克洋，樋口貴史，阿部健作，谷口裕太，相羽 久輝，荒木 麗博，土屋弘行
  • Organizer: 第50回日本整形外科学会 骨・軟部腫瘍学術集会
• [Presentation] 小児膝関節周囲骨肉腫に対する関節温存再建術後の骨端の成長 (2017)
  • Author(s): 武内章彦，山本憲男，林 克洋，樋口貴史，阿部健作，谷口裕太，相羽 久輝，荒木 麗博，土屋弘行
  • Organizer: 第50回日本整形外科学会 骨・軟部腫瘍学術集会
• [Presentation] Epiphyseal growth of the knee joint after epiphysis-preservation surgery for childhood (2017)
  • Author(s): Takeuchi A, Yamamoto N, Hayashi K, Higuchi T, Abe K, Taniguchi Y, Aiba H, Tsuchiya H
  • Organizer: 第90回日本整形外科学会学術集会
• [Presentation] 骨巨細胞腫に対するデノスマブ投与後の骨形成のメカニズムに関する解析 (2017)
  • Author(s): 武内章彦，山本憲男，村上英樹，林 克洋，樋口貴史，阿部健作，谷口裕太，相羽 久輝，荒木 麗博，土屋弘行
  • Organizer: 第32回日本整形外科基礎学術集会
• [Presentation] Epiphysis growth of the knee joint after epiphyseal-preservation surgery for childhood osteosarcoma (2017)
  • Author(s): Takeuchi A, Yamamoto N, Hayashi K, Higuchi T, Abe K, Taniguchi Y, Aiba H, Araki Y, Tsuchiya H
  • Organizer: 19th International Society of Limb Salvage meeting
  • Int'l Joint Research
• [Presentation] Feasibility as novel treatment of Zaltoprofen for diffuse-type tenosynovial giant cell tumor arising in knee and ankle joint: A pilot study. (2017)
  • Author(s): Takeuchi A, Yamamoto N, Hayashi K, Higuchi T, Abe K, Taniguchi Y, Aiba H, Tsuchiya H
  • Organizer: 19th International Society of Limb Salvage meeting
  • Int'l Joint Research
• [Presentation] Pathogenesis Of osteosclerotic change following anti-RANKL antibody (Denosumab) treatment for giant cell tumor of bone: Where does it come from? (2017)
  • Author(s): Takeuchi A, Rosario M, Yamamoto N, Hayashi K, Higuchi T, Abe K, Taniguchi Y, Aiba H, Murakami H, Tsuchiya H
  • Organizer: 18th European Federation of National Associations of Orthopaedics and Traumatology meeting
  • Int'l Joint Research
• [Presentation] Epiphysis growth of the knee joint after epiphyseal preservation surgery for childhood osteosarcoma (2017)
  • Author(s): Takeuchi A, Yamamoto N, Hayashi K, Higuchi T, Abe K, Taniguchi Y, Aiba H, Tsuchiya H
  • Organizer: 18th European Federation of National Associations of Orthopaedics and Traumatology meeting
  • Int'l Joint Research