Inhibition of the Hedgehog pathway prevents human rhabdomyosarcoma cell growth

• Project/Area Number: 24592238
• 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: KAWABATA Naoya 鹿児島大学, 医歯(薬)学総合研究科, 客員研究員 (60626836)
• Co-Investigator(Kenkyū-buntansha): KOMIYA Setsuro 鹿児島大学, 大学院医歯学総合研究科, 教授 (30178371) ; SETOGUCHI Takao 鹿児島大学, 大学院医歯学総合研究科, 特任准教授 (40423727) ; NAGANO Satoshi 鹿児島大学医学部, 歯学部附属病院, 講師 (50373139) ; ABEMATSU Masahiko 鹿児島大学医学部, 歯学部附属病院, 助教 (70448190) ; TANABE Fumito 鹿児島大学医学部, 歯学部附属病院, 助教 (90619199)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 横紋筋肉腫 / Hedgehog / GLI2 / 骨肉腫 / 骨軟部肉腫 / 転移 / Notch / RBPJ

Outline of Final Research Achievements

We investigated the expression and function of the Hedgehog pathway. Real-time PCR revealed that human rhabdomyosarcoma cell lines and biopsy specimens overexpressed the following genes: Sonic hedgehog, Indian hedgehog, Desert hedgehog, PTCH1, SMO, GLI1, GLI2 and ULK3. Immunohistochemistry revealed that rhabdomyosarcoma cell lines and biopsy specimens expressed SMO and GLI2. Inhibition of SMO by cyclopamine slowed the growth of human rhabdomyosarcoma cell lines. Similarly, inhibition of GLI by GANT61 slowed the growth of human rhabdomyosarcoma cell lines. Inhibition of cell proliferation and apoptotic cell death together prevented the growth of rhabdomyosarcoma cells by cyclopamine and GANT61 treatment. In addition, knockdown of GLI2 inhibited invasion of osteosarcoma cell and decreased lung metastasis of osteosarcomas. Our findings suggest that inhibition of the Hedgehog pathway may be a useful approach for treating rhabdomyosarcoma and osteosarcoma patients.

Research Products

• [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
• [Journal Article] RBPJ Is a Novel Target for Rhabdomyosarcoma Therapy. (2012)
  • Author(s): Hiroko Nagao, Takao Setoguchi, Sho Kitamoto, Yasuhiro Ishidou, Satoshi Nagano, Masahiro Yokouchi, Masahiko Abematsu, Naoya Kawabata, Shingo Maeda, Suguru Yonezawa, Setsuro Komiya
  • Journal Title: PLoS ONE Volume: 7(7) Issue: 7 Pages: e39268-e39268
  • DOI: 10.1371/journal.pone.0039268
  • Peer Reviewed