EGFR遺伝子変異陽性非小細胞肺癌におけるCD44バリアント依存性のレドックスバランス制御 : CD44vを標的とした治療戦略 - 九大コレクション | 九州大学附属図書館

＜博士論文＞
EGFR遺伝子変異陽性非小細胞肺癌におけるCD44バリアント依存性のレドックスバランス制御 : CD44vを標的とした治療戦略

	CD44 variant-dependent regulation of redox balance in EGFR mutation-positive non-small cell lung cancer: A target for treatment
作成者	作成者姓名土屋（河野）裕子 Tsuchiya(Kawano) , Yuko ツチヤ（カワノ）, ユウコ
論文調査委員	前原, 喜彦
	赤司, 浩一
	康, 東天
本文言語	英語
学位授与年度	2017
学位授与大学	九州大学
学位授与大学	Kyushu University
学位	博士（医学）
学位種別	課程博士
アクセス権	metadata only access
関連DOI	https://doi.org/10.1016/j.lungcan.2017.09.008
概要	OBJECTIVES:The regulation of redox balance in cancer cells is an important factor in tumor development and chemoresistance, with oncogene activation having been shown to induce the generation of react...ive oxygen species (ROS). 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 ROS generation in NSCLC cells. MATERIALS AND METHODS:HEK293T cells were transfected with an expression vector for mutant EGFR. The expression of CD44 variant (CD44v) isoforms in NSCLC cell lines was evaluated by flow cytometry. Cells were depleted of CD44v by RNA interference and assayed for ROS and glutathione (GSH) levels. The effect of CD44v on cisplatin sensitivity was evaluated in vitro with the MTS assay. RESULTS:EGFR signaling due to EGFR mutation increased ROS levels in transfected HEK293T cells. The expression of CD44v isoforms was found to be inversely correlated with basal ROS levels in EGFR mutation-positive NSCLC cell lines. Knockdown of CD44v induced depletion of intracellular GSH and increased ROS levels in EGFR-mutated NSCLC cells that express CD44v at a high level (CD44vhigh). In addition, depletion of GSH by treatment with buthionine-[S, R]-sulfoximine induced marked accumulation of ROS and enhanced the cytotoxicity of cisplatin in CD44vhighEGFR-mutated NSCLC cells but not in corresponding CD44vlow cells. This enhancement of cisplatin cytotoxicity by GSH depletion was prevented by treatment with the antioxidant N-acetyl-l-cysteine. Knockdown of CD44v also enhanced cisplatin cytotoxicity in CD44vhighEGFR mutation-positive NSCLC cells but not in CD44vlow cells. CONCLUSION:Our results thus implicate CD44v in redox adaptation and as a potential target for treatment in CD44vhighEGFR-mutated NSCLC cells.続きを見る

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med3080_abstract	pdf	119 KB	516	要旨
med3080_summary	pdf	111 KB	149	要約
med3080_review	pdf	167 KB	154	審査結果要旨

詳細

レコードID	1931766
査読有無	査読有
権利関係	やむを得ない事由により本文ファイル非公開 (2)
権利関係	Public access to the fulltext file is restricted for unavoidable reason (2)
関連PubMed ID	29110853
報告番号	17102甲第13913号
学位記番号	医博甲第3080号
授与日(学位/助成/特許)	2018-02-28
受理日	2018-02-14
部局	医博
登録日	2018.05.30
更新日	2018.08.31