Research for Molecular Target of Osteosarcoma treatment

• Project/Area Number: 25462342
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Kagoshima University
• Principal Investigator: Setoguchi Takao 鹿児島大学, 医歯(薬)学総合研究科, 特任准教授 (40423727)
• Co-Investigator(Kenkyū-buntansha): KOMIYA Setsuro 鹿児島大学, 医歯学域医学系, 教授 (30178371) ; NAGANO Satoshi 鹿児島大学, 医歯学域医学系, 准教授 (50373139)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 骨肉腫 / Hedgehog / GLI2 / RPS3 / metastasis / 三酸化ヒ素

Outline of Final Research Achievements

We researched the molecular target for osteosarcoma treatment. We found that Hedgehog pathway is upregulated in human osteosarcoma. Inhibition of GLI family zinc finger 2 (GLI2) prevent osteosarcoma invasion. Invasion assay showed that combination of arsenic trioxide (ATO) and vismodegib (SMO inhibitor) prevented invasion of human osteosarcoma cells. Xenograft model showed that combination of ATO and vismodegib prevented lung metastasis of osteosarcoma. We found that expression of ribosomal protein S3 (RPS3) is regulated by GLI2. RPS3 promoted the invasion of osteosarcoma cells. These findings suggest that GLI2-RPS3 pathway might be a new therapeutic target for osteosarcoma.

Research Products

• [Journal Article] Combination of Hedgehog inhibitors and standard anticancer agents synergistically prevent osteosarcoma growth. (2016)
  • Author(s): Saitoh Y, Setoguchi T, Nagata M, Tsuru A, Nakamura S, Nagano S, Ishidou Y, Nagao-Kitamoto H, Yokouchi M, Maeda S, Tanimoto A, Furukawa T, Komiya S.
  • Journal Title: Int J Oncol. Volume: 48 Issue: 1 Pages: 235-42
  • DOI: 10.3892/ijo.2015.3236
  • Peer Reviewed
• [Journal Article] Hairy/enhancer-of-split related with YRPW motif protein 1 promotes osteosarcoma metastasis via matrix metallopeptidase 9 expression. (2015)
  • Author(s): Tsuru A, Setoguchi T, Matsunoshita Y, Nagao-Kitamoto H, Nagano S, Yokouchi M, Maeda S, Ishidou Y, Yamamoto T, Komiya S.
  • Journal Title: Br J Cancer. Volume: 112 Issue: 7 Pages: 1232-40
  • DOI: 10.1038/bjc.2015.84
  • Peer Reviewed / Open Access
• [Journal Article] Ribosomal protein S3 regulates GLI2-mediated osteosarcoma invasion. (2015)
  • Author(s): Nagao-Kitamoto H, Setoguchi T, Kitamoto S, Nakamura S, Tsuru A, Nagata M, Nagano S, Ishidou Y, Yokouchi M, Kitajima S, Yoshioka T, Maeda S, Yonezawa S, Komiya S.
  • Journal Title: Cancer Lett. Volume: 356 Issue: 2 Pages: 855-861
  • DOI: 10.1016/j.canlet.2014.10.042
  • Peer Reviewed
• [Journal Article] GLI2 is a novel therapeutic target for metastasis of osteosarcoma. (2015)
  • Author(s): Nagao-Kitamoto H, Nagata M, Nagano S, Kitamoto S, Ishidou Y, Yamamoto T, Nakamura S, Tsuru A, Abematsu M, Fujimoto Y, Yokouchi M, Kitajima S, Yoshioka T, Maeda S, Yonezawa S, Komiya S, Setoguchi T.
  • Journal Title: Int J Cancer. Volume: 136 Issue: 6 Pages: 1276-1284
  • DOI: 10.1002/ijc.29107
  • Peer Reviewed / Open Access
• [Journal Article] Survivin-responsive conditionally replicating adenovirus kills rhabdomyosarcoma stem cells more efficiently than their progeny (2014)
  • Author(s): Tanoue K, Wang Y, Ikeda M , Mitsui K, Irie R , Setoguchi T, Komiya S, Natsugoe S, Kosai K
  • Journal Title: J Trans Med Volume: 12 Issue: 1 Pages: 27-27
  • DOI: 10.1186/1479-5876-12-27
  • Peer Reviewed / Open Access
• [Journal Article] Arsenic trioxide prevents osteosarcoma growth by inhibition of GLI transcription via DNA damage accumulation. (2013)
  • Author(s): Nakamura S, Nagano S, Nagao H, Ishidou Y, Yokouchi M, Abematsu M, Yamamoto T, Komiya S, Setoguchi T.
  • Journal Title: PLoS One Volume: 8 Issue: 7 Pages: e69466-e69466
  • DOI: 10.1371/journal.pone.0069466
  • NAID: 120005324788
  • Peer Reviewed
• [Presentation] Combination use of Hedgehog inhibitors prevent osteosarcoma growth synergistically (2016)
  • Author(s): Saitoh Y., Setoguchi T., Nagata M., Nakamura S., Nagano S., Ishidou Y., Komiya S.
  • Organizer: 62th Annual Meeting of the Orthopaedic Research Society
  • Place of Presentation: Orland USA
  • Year and Date: 2016-03-05
  • Int'l Joint Research
• [Presentation] 骨軟部肉腫に対する分子標的治療研究 (2014)
  • Author(s): 瀬戸口啓夫
  • Organizer: 第87回日本整形外科学会学術総会
  • Place of Presentation: 神戸
  • Invited
• [Presentation] GLI2によるRPS3発現を介した骨肉腫転移能亢進 (2013)
  • Author(s): 瀬戸口啓夫
  • Organizer: 日本整形外科学会基礎学術集会
  • Place of Presentation: 千葉
• [Presentation] 骨軟部肉腫における分子標的治療研究 (2013)
  • Author(s): 瀬戸口啓夫
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Invited