Analysis of the mechanism of hypoxia stress response in adult t-cell leukemia (ATL)

• Project/Area Number: 16K07120
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: University of Miyazaki
• Principal Investigator: Nakahata Shingo 宮崎大学, 医学部, 講師 (80437938)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 低酸素 / NDRG2 / ATL / 低酸素ストレス / 成人T細胞白血病 / PI3K/AKT / オートファジー / 癌

Outline of Final Research Achievements

This study suggested that, as a response to hypoxia, the regulation of phosphorylation of cellular signaling molecules by NDRG2 plays an important role in the growth of cancer cells. NDRG2 regulates various signaling pathways including PI3K/AKT and NF-κB. This study also suggested NDRG2 is involved in the function of hematopoietic stem cells (HSCs) and may play a role in the regulation of hypoxia response of HSCs in the bone marrow niche. In addition, the downregulation of p47 expression via the autophagy-lysosome pathway contributes to the activation of NF-κB in ATL.

Academic Significance and Societal Importance of the Research Achievements

癌抑制遺伝子として同定したNDRG2が癌の低酸素適応・抵抗性の機構解明の鍵となる分子であることを示唆した。またNDRG2は、低酸素幹細胞ニッチでの機能にも役割を果たす可能性が示され、がん幹細胞を含めた更なるその制御機構の解明により、新規分子標的薬の開発につながる可能性が示唆された。

Research Products

• [Journal Article] Degradation of p47 by autophagy contributes to CADM1 overexpression in ATLL cells through the activation of NF-κB. (2019)
  • Author(s): Sarkar B, Nishikata I, Nakahata S, Ichikawa T, Shiraga T, Saha HR, Fujii M, Tanaka Y, Shimoda K, Morishita K.
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 3491-3491
  • DOI: 10.1038/s41598-019-39424-7
  • NAID: 120006825908
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] ATLにおけるオートファジーによるNF-κB負の制御因子p47の不活化は、NF-κBシグナルを増強しCADM1高発現をもたらす (2018)
  • Author(s): 中畑新吾、Bidhan Sarkar、西片一郎、市川朝永、藤井雅寛、井上純一郎、伊波英克、下田和哉、森下和広
  • Organizer: 第91回日本生化学会大会
• [Presentation] ATLにおけるNDRG2発現低下は細胞ストレス応答異常に関与する (2017)
  • Author(s): 中畑新吾、市川朝永、斎藤祐介、滝智彦、谷脇雅史、森下和広
  • Organizer: 第4回日本HTLV-1学会
• [Presentation] ATLLにおけるNDRG2発現低下はPI3K/AKTシグナルの恒常的活性化を介して低酸素抵抗性を来す (2016)
  • Author(s): 中畑新吾、市川朝永、斎藤祐介、滝智彦、谷脇雅史、森下和広
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2016-11-30
• [Presentation] NDRG2 down-regulation induces hypoxic resistance via activation of PI3K/AKT signaling in ATLL. (2016)
  • Author(s): Singo Nakahata, Tomonaga Ichikawa, Yusuke saito, Tomokiko Taki, Masafumi Taniwaki, Kazuhiro Morishita
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2016-10-13
• [Presentation] NDRG2 regulates the cell growth response to hypoxia via control of the PI3K/AKT pathway. (2016)
  • Author(s): Shingo Nakahata, Tomonaga Ichikawa, Yusuke Saito, Tomohiko Taki, Masafumi Taniwaki, Kazuhiro Morishita.
  • Organizer: The 5th JCA-AACR Special Joint Conference
  • Place of Presentation: 千葉県浦安市
  • Year and Date: 2016-07-13
  • Int'l Joint Research