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

2017 Fiscal Year Annual Research Report

• Project/Area Number: 15K10435
• Research Institution: Kanazawa University
• Principal Investigator: 武内 章彦 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)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 骨肉腫 / 幹細胞 / 糖化蛋白受容体

Outline of Annual Research Achievements

RAGE過剰発現ヒト骨肉種細胞株(HOS-RAGE細胞株)と対称のmock導入ヒト骨肉種細胞株(HOS-mock細胞株)において、平成23-25年度に若手B研究によりHOS-RAGE細胞株では、Genechipによる発現遺伝子解析で有意に変化する遺伝子(主に細胞周期に関わるもの)を複数見出したが、spheroidを形成した状態がより幹細胞の性質に近いと考え、その条件を用いて、平成28年度に網羅的miRNA解析を施行した。その結果有意に増加するmiRNAと低下するmiRNAを30個見いだすことができた。平成29年度は、その中でmiR-34aの発現がHOS-RAGE細胞株において有意に低下していることに注目し、HOS-RAGE細胞株とHOS-mock細胞株のRNAを用いてリアルタイムPCRでmiR-34aの発現を解析すると、HOS-RAGE細胞株のmiR-34aの発現がHOS-mock細胞株よりも有意に低いことを確認した。miR-34aは他の癌腫においてSOX2, NANOG, N-MYC といった多能性遺伝子を制御することやがん抑制遺伝子である p53によって転写活性化されることが報告されており、これまでの解析で見出したSOX2, NANOG, MYCの発現に関わっている可能性が示唆された。そこで、RAGEがmiR-34aの発現抑制にどのように関わっているかさらなる解析を進めている。

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 Pages: 印刷中
  • DOI: 10.1002/cam4.1438
  • 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 AHAM, Munesue S, Harashima A, Sato A, Shindo M, Nakajima S, Inada M, Tanaka M, Takeuchi A, Tsuchiya H, Yamamoto H, Shaheen HME, El-Sayed YS, Kawano S, Tanuma SI, Yamamoto Y
  • Journal Title: Oncol Lett. Volume: 15 Pages: 4627-34
  • DOI: 10.3892/ol.2018.7902
  • Peer Reviewed
• [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 Pages: 印刷中
  • 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 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: 475 Pages: 1693-1701
  • DOI: 10.1007/s11999-017-5259-z
  • Peer Reviewed
• [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