Functional role of PPP3CB in neuroblastoma and potential anti-tumor effect of calcineurin inhibitor on neuroblastoma

• Project/Area Number: 15K10933
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatric surgery
• Research Institution: 地方独立行政法人佐賀県医療センター好生館(ライフサイエンス研究所)
• Principal Investigator: LI YUANYUAN 地方独立行政法人佐賀県医療センター好生館(ライフサイエンス研究所), ライフサイエンス研究所, 研究員 (00392259)
• Co-Investigator(Kenkyū-buntansha): 中川原 章 地方独立行政法人佐賀県医療センター好生館(ライフサイエンス研究所), ライフサイエンス研究所, 理事長 (50117181)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 神経芽腫 / PPP3CB / calcineurin inhibitor / ＰＰＰ３ＣＢ

Outline of Final Research Achievements

PPP3CB is the catalytic subunit of calcineurin, a calcium-dependent serine/threonine phosphatase. In this study we found that overexpression of wildtype PPP3CB or constitutively active PPP3CB mutant (PPP3CBmut) identified from a neuroblastoma (NB) tumor promoted cell growth in NB cells. PPP3CB and PPP3CBmut activated nuclear factor of activated T-cells (NFAT)2 /NFAT4 transcription factors, Akt and MAPK signaling, resulting in the increase in the expressions of c-Myc, MYCN and β-catenin. Treatment with calcineurin inhibitors (CaIs) suppressed cell proliferation and induced apoptotic cell death in several NB cell lines. Expression of PPP3CB along with those of c-Myc, MYCN and β-catenin was decreased in response to CaIs. Our findings demonstrate that PPP3CB contributes to the aggressive behavior of NB tumors and CaIs have a strong anti-tumor activity in vitro by targeting PPP3CB, suggesting that inhibition of calcineurin activity might have therapeutic potential for high-risk NBs.

Research Products

• [Journal Article] Neuroblastoma (2018)
  • Author(s): Nakagawara Akira、Li Yuanyuan、Izumi Hideki、Muramori Katsumi、Inada Hiroko、Nishi Masanori
  • Journal Title: Jpn. J. Clin. Oncol. Volume: 48 Issue: 3 Pages: 214-241
  • DOI: 10.1093/jjco/hyx176
  • Peer Reviewed
• [Journal Article] Genomic analysis–integrated whole-exome sequencing of neuroblastomas identifies genetic mutations in axon guidance pathway (2017)
  • Author(s): Li Yuanyuan、Ohira Miki、Zhou Yong、Xiong Teng、Luo Wen、Yang Chao、Li Xiangchun、Gao Zhibo、Zhou Rui、Nakamura Yohko、Kamijo Takehiko、Kaneko Yasuhiko、Taketani Takeshi、Ueyama Junichi、Tajiri Tatsuro、Zhang Hongyan、Wang Jian、Yang Huanming、Yin Ye、Nakagawara Akira
  • Journal Title: Oncotarget Volume: 8 Issue: 34 Pages: 56684-56697
  • DOI: 10.18632/oncotarget.18079
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Familial neuroblastoma（家族性神経芽腫） (2015)
  • Author(s): 李元元, 木下儀晶, 中川原章
  • Journal Title: 日本臨牀 Volume: 73(1083) Pages: 108-114
• [Presentation] Genomic Analysis-Integrated Whole-exome Sequencing of Neuroblastomas (2017)
  • Author(s): Li Y and Nakagawara A
  • Organizer: The 3rd China International Forum of Pediatric Development
  • Invited
• [Presentation] PPP3CB is a novel prognostic indicator of high-risk neuroblastoma contributing to aggressive behaviors. (2016)
  • Author(s): Yuanyuan Li, Irina Shakhova, Miki Ohira, Yohko Nakamura, Svetlana R. Varfolomeeva, Alexander G. Rumyantsev and Akira Nakagawara.
  • Organizer: Advances in Neuroblastoma Research (ANR)
  • Place of Presentation: Cairns, Australia
  • Year and Date: 2016-06-19
  • Int'l Joint Research