Analysis of NR4A2-associated mechanism of anti-cancer drug resistance in salivary gland cancer stem cells.

• Project/Area Number: 16K11684
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Hiroshima University
• Principal Investigator: Ishioka Yasuki 広島大学, 病院(歯), 歯科診療医 (70770840)
• Co-Investigator(Kenkyū-buntansha): 小野 重弘 広島大学, 医歯薬保健学研究科(歯), 助教 (70379882) ; 重石 英生 広島大学, 医歯薬保健学研究科(歯), 講師 (90397943)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 唾液腺癌 / アポトーシス / NR4A2 / 癌幹細胞 / 唾液腺癌幹細胞 / 抗癌剤抵抗性

Outline of Final Research Achievements

We examined 5-FU-induced apoptosis in sorted cell populations (i.e., CD44high/ESAlow, CD44high/ESAhigh, and CD44low cells from the salivary gland carcinoma cells) to clarify the anti-apoptotic effect of exogenous PGE2. CD44high/ESAlow cells contribute to induction of resistance to 5-FU in CD44high/ESAhigh cells through provision of PGE2.

Academic Significance and Societal Importance of the Research Achievements

唾液腺癌における抗癌剤抵抗性のメカニズムについては十分に解明されていない。今回の研究結果から、CD44high/ESAlow細胞が産生するPGE2が、CD44high/ESAhigh細胞の5-FUにより誘導されるアポトーシスの抵抗性に関与することが明らかとなった。このことから、 唾液腺癌細胞における、外因性の液性因子及びNR4A2等の転写因子を介した、特徴的な抗癌剤抵抗性メカニズムの存在が示唆された。

Research Products

• [Journal Article] CD44high/ESAlow squamous cell carcinoma cell-derived prostaglandin E2 confers resistance to 5-fluorouracil-induced apoptosis in CD44high/ESAhigh cells (2018)
  • Author(s): Shigeishi H, Hashikata M, Yokoyama S, Sakuma M, Murozumi H, Kato H, Rahman MZ, Seino S, Ishioka Y, Ohta K, Takechi M, Sugiyama M
  • Journal Title: International Journal of Clinical and Experimental Pathology Volume: 11 Pages: 2356-2363
  • Peer Reviewed / Open Access
• [Journal Article] CD44high /ALDH1high head and neck squamous cell carcinoma cells exhibit mesenchymal characteristics and GSK3β-dependent cancer stem cell properties. (2016)
  • Author(s): Seino S, Shigeishi H, Hashikata M, Higashikawa K, Tobiume K, Uetsuki R, Ishida Y, Sasaki K, Naruse T, Rahman MZ, Ono S, Simasue H, Ohta K, Sugiyama M, Takechi M.
  • Journal Title: J Oral Pathol Med. Volume: 45(3) Pages: 180-188
  • Peer Reviewed
• [Journal Article] Snail-induced CD44high cells in HNSCC with high ABC transporter capacity exhibit potent resistance to cisplatin and docetaxel. (2016)
  • Author(s): Hashikata M, Shigeishi H, Okui G, Yamamoto K, Tobiume K, Seino S, Uetsuki R, Kato H, Ishioka Y, Ono S, Ohta K, Higashikawa K, Sugiyama M, Takechi M.
  • Journal Title: Int J Clin Exp Pathol. Volume: 9(8) Pages: 7908-7918
  • Peer Reviewed