Epidermal growth factor signals regulate dihydropyrimidine dehydrogenase expression in EGFR-mutated non-small-cell lung cancer

• Project/Area Number: 26462130
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory surgery
• Research Institution: Nagasaki University
• Principal Investigator: NAGAYASU Takeshi 長崎大学, 医歯薬学総合研究科(医学系), 教授 (80284686)
• Co-Investigator(Kenkyū-buntansha): 土谷 智史 長崎大学, 医歯薬学総合研究科(医学系), 准教授 (30437884) ; 日高 重和 長崎大学, 病院(医学系), 講師 (30380885)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 非小細胞肺癌 / Sp1 / DPD / EGFR / NSCLC / Gefitinib

Outline of Final Research Achievements

It has been shown that EGFR mutation status is associated with 5-FU sensitivity in non-small-cell lung cancer (NSCLC). However, the relationship between EGFR
mutation status and DPD, a 5-FU degrading enzyme, is unknown. In EGFR mutated cell, EGF treatment induced up-regulation of both Sp1 and DPD. EGFR-TKI and mithramycin A, a specific Sp-1 inhibitor, suppressed them. EGFR-TKI inhibited DPD protein expression only in EGFR-mutated cell lines. FU treatment decreased the level of cell viability more in gefitinib-treated EGFR-TKI sensitive cell lines. Further, combination treatment of FU and mithramycin A suppressed cell viability even in a gefitinib resistant cell line. The EGFR signal cascade regulates DPD expression via Sp1 in EGFR mutant cells. These results might be a step towards new therapies targeting Sp1 and DPD in NSCLC with different EGFR mutant status.

Research Products

• [Journal Article] Epidermal growth factor signals regulate dihydropyrimidine dehydrogenase expression in EGFR-mutated non-small-cell lung cancer (2016)
  • Author(s): Tetsuro Tominaga
  • Journal Title: BMC cancer Volume: 16 Pages: 354-354
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 非小細胞肺癌にｐけるEGR変異とDPDおよびその関連因子に関する検討 (2015)
  • Author(s): 富永哲郎,土谷智史,朝重耕一,畑地 豪,荒井淳一,宮﨑拓郎,松本桂太郎,山崎直哉,永安 武
  • Organizer: 日本臨床分子形態学会
  • Place of Presentation: 長崎大学(長崎県長崎市)
  • Year and Date: 2015-09-19
• [Presentation] 非小細胞肺癌におけるEGFR変異とDPDおよびその関連因子に対する検討 (2014)
  • Author(s): 富永哲郎
  • Organizer: 九州肺癌カンファランス
  • Place of Presentation: アクロス福岡（福岡県）
  • Year and Date: 2014-07-12
• [Presentation] Epidermal Growth Factor Signals Regulate Dihydropyrimidine Dehydrogenase Expression in Non-Small-Cell Lung Cancer (2014)
  • Author(s): 富永哲郎
  • Organizer: 日本外科学会
  • Place of Presentation: 国立京都国際会館（京都府）
  • Year and Date: 2014-04-03 – 2014-04-05