Understanding molecular mechanism underlying innate immune system escape for metastasis in sarcoma

• Project/Area Number: 15K10458
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: 医療法人徳洲会野崎徳洲会病院(附属研究所) (2016-2017); Research Institute, Osaka Medical Center for Cancer and Cardiovascular Disaeses (2015)
• Principal Investigator: Sasagawa Satoru 医療法人徳洲会野崎徳洲会病院(附属研究所), 研究所, 部長 (80345115)
• Research Collaborator: ITOH Kazuyuki 医療法人徳洲会野崎徳洲会病院, 検診センター, センター長 (20301806)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 滑膜肉腫 / 転移 / 自然免疫応答 / 転移の分子メカニズム / Twist1

Outline of Final Research Achievements

In this study，we focused on the mechanism how the synovial sarcoma cells escape from immune surveillance and found that MICA/B molecules in synovial sarcoma cells were disappeared when the cells were in hypoxia and floating conditions. Twist1 transcription factor also depressed MICA/B expression. On the other hand, low-dose of HDAC inhibitors markedly up-regulated MICA/B expression. MICA/B expression was N-glycosylation sensitive and tunicamycin treatment rapidly killed MICA/B expression. We also found that MICA/B negative synovial sarcoma cells was also sensitive to HDAC inhibitor treatment and confirmed weak MICA/B protein expression. Here, we found that MICA/B mRNA sequence in MICA/B negative cells were not uniform and most of that disrupted N-glycosylation site in protein level. In conclusion, low-dose of HDAC inhibitor treatment could improve anti-tumor-effect by NK cells by MICA/B stimulation.

Research Products

• [Journal Article] Evidence for intrathecal sodium butyrate as a novel option for leptomeningeal metastasis. (2018)
  • Author(s): Nakagawa H, Yui Y, Sasagawa S, Itoh K.
  • Journal Title: Journal of Neuro-Oncology Volume: 印刷中 Issue: 1 Pages: 43-50
  • DOI: 10.1007/s11060-018-2852-2
  • Peer Reviewed
• [Journal Article] Sodium butyrate induces senescence and inhibits the invasiveness of glioblastoma cells. (2018)
  • Author(s): Nakagawa H, Sasagawa S, Itoh K.
  • Journal Title: Oncology letter Volume: 15(2) Pages: 1495-1502
  • DOI: 10.3892/ol.2017.7518
  • Peer Reviewed / Open Access
• [Journal Article] Trabectedin is a promising antitumour agent for synovial sarcoma (2016)
  • Author(s): Yasui, H., Imura, Y., Outani, H., Hamada, K., Nakai, T., Yamada, S., Takenaka, S., Sasagawa, S., Araki, N., Itoh, K., Myoui, A., Yoshikawa, H., & Naka, N.
  • Journal Title: Journal of Chemotherapy Volume: e-pub ahead of print Issue: 5 Pages: 1-8
  • DOI: 10.1080/1120009x.2015.1133013
  • Peer Reviewed
• [Journal Article] Trabectedin is a promising antitumour agent for synovial sarcoma (2016)
  • Author(s): Takaaki Nakai, Shutaro Yamada, Satoshi Takenaka, Satoru Sasagawa, Nobuhito Araki, Kazuyuki Itoh, Akira Myoui, Hideki Yoshikawa, Norifumi Naka
  • Journal Title: Journal of Chemotherapy Volume: e-pub ahead of print
  • Peer Reviewed
• [Journal Article] Taspase1-dependent TFIIA cleavage coordinates head morphogenesis by limiting Cdkn2a locus transcription. (2015)
  • Author(s): Takeda S, Sasagawa S, Oyama T, Searleman AC, Westergard TD, Cheng EH, Hsieh JJ.
  • Journal Title: The Journal of Clinical Investigation Volume: 125(3) Issue: 3 Pages: 1203-1214
  • DOI: 10.1172/jci77075
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Analysis of metastatic potential regulated by Twist1 in synovial sarcoma (2017)
  • Author(s): Satoru Sasagawa, Yoshihiro Yui, Kenta Watanabe, Hidemitsu Nakagawa, Kazuyuki Itoh.
  • Organizer: 日本癌学会 第76回学術総会
• [Presentation] Regulation of Metastatic Potential by Twist1 in Sarcoma (2016)
  • Author(s): S. Sasagawa, Y. Yui, H. Nakagawa, K. Itoh
  • Organizer: 日本癌学会
  • Place of Presentation: 横浜（パシフィコ横浜）
  • Year and Date: 2016-10-06