Functional analysis of cancer stem cell marker CD44v in EGFR-mutated non-small cell lung cancer

• Project/Area Number: 15K06874
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Kyushu University
• Principal Investigator: Okamoto Isamu 九州大学, 大学病院, 講師 (10411597)
• Co-Investigator(Kenkyū-buntansha): 原田 大志 九州大学, 大学病院, 助教 (10380619) ; 中西 洋一 九州大学, 大学病院, 教授 (20172356) ; 岩間 映二 九州大学, 医学研究院, 助教 (40567343) ; 田中 謙太郎 九州大学, 医学(系)研究科(研究院), 助教 (00536849)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: CD44バリアント(CD44v) / 活性酸素 / 上皮成長因子受容体(EGFR) / 非小細胞肺癌 / グルタチオン / 抗癌剤感受性 / レドックスバランス / EGFR遺伝子変異 / ROS / CD44 / 肺癌 / EGFR遺伝子 / 癌幹細胞

Outline of Final Research Achievements

Activating mutations of the epidermal growth factor receptor gene (EGFR) are oncogenic drivers in non-small cell lung cancer (NSCLC), but it has remained unknown whether ligand-independent EGFR signaling conferred by EGFR mutation triggers reactive oxygen species (ROS) generation in NSCLC cells. We showed EGFR signaling due to EGFR mutation increased ROS levels. The expression of CD44v isoforms was found to be inversely correlated with basal ROS levels in EGFR-mutated NSCLC cell lines. Knockdown of CD44v induced depletion of intracellular glutathione (GSH) and increased ROS levels in EGFR-mutated NSCLC cells that express CD44v at a high level (CD44vhigh). In addition, depletion of GSH enhanced the cytotoxicity of cisplatin in CD44vhigh EGFR-mutated NSCLC cells. Knockdown of CD44v also enhanced cisplatin cytotoxicity in CD44vhigh EGFR- mutated NSCLC cells. Our results thus implicate CD44v in redox adaptation and as a potential target for treatment in CD44vhigh EGFR-mutated NSCLC cells.

Research Products

• [Journal Article] CD44 variant dependent regulation of redox balance in EGFR mutation-positive non-small cell lung cancer: A target for treatment (2017)
  • Author(s): Kawano Y., Iwama E., Tsuchihashi K., Shibahara D., Harada T., Tanaka K., Nagano O., Saya H., Nakanishi Y. & Okamoto I.
  • Journal Title: Lung Cancer Volume: 113 Pages: 72-78
  • DOI: 10.1016/j.lungcan.2017.09.008
  • Peer Reviewed
• [Presentation] EGFR遺伝子変異陽性非小細胞肺癌における、CD44ｖ、EGFRシグナルを介した活性酸素制御 (2016)
  • Author(s): 河野裕子、岡本勇、岩間映二、原田大志、土橋賢司、永野修、佐谷秀行、中西洋一
  • Organizer: がん分子標的治療学会
  • Place of Presentation: 大分県別府
  • Year and Date: 2016-05-30
• [Presentation] EGFR遺伝子変異陽性非小細胞肺癌における、CD44v、EGFRシグナルを介した活性酸素制御 (2016)
  • Author(s): 河野裕子、岡本勇、岩間映二、原田大志、土橋賢司、永野修、佐谷秀行、中西洋一
  • Organizer: がん分子標的治療学会
  • Place of Presentation: 大分県別府
  • Year and Date: 2016-05-30
• [Presentation] Expression of CD44 variants in EGFR-mutation positive non-small cell lung cancer (NSCLC) (2015)
  • Author(s): 河野裕子、岡本勇
  • Organizer: 日本癌学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08