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系統識別號 U0026-3101201322322000
論文名稱(中文) 人類角質細胞中活性氧化物參與在三氧化二砷透過 c-Src 轉錄活化 EGFR 所調控 p21WAF1/CIP1 基因表現
論文名稱(英文) ROS mediates EGFR transactivation by c-Src in arsenic trioxide-regulated p21WAF1/CIP1gene expression in human keratinocytes
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 101
學期 1
出版年 102
研究生(中文) 曾鴻裕
研究生(英文) Hong-Yu Tseng
學號 S58941078
學位類別 博士
語文別 英文
論文頁數 106頁
口試委員 指導教授-黃暉升
召集委員-莊季瑛
口試委員-劉校生
口試委員-凌斌
口試委員-余幸司
口試委員-劉怡文
中文關鍵字 三氧化二砷  活性氧化物 
英文關鍵字 arsenic trioxide  Src  NADPH oxidase  EGFR  reactive oxygen species 
學科別分類
中文摘要 雖然砷 (arsenic) 為一種已知的致癌物質,但是砷也被做為治療急性骨髓前白血病的藥物以及促進腫瘤細胞株的死亡。根據刺激細胞濃度的不同,砷對於細胞有促進癌化或是死亡的不同影響。在實驗室先前研究中發現,砷透過活化 c-Src/EGFR/ERK 訊息傳遞路徑以及增加活性氧化物 (ROS) 的產生以促進 p21WAF1/CIP1 (p21) 蛋白質表現並誘發細胞死亡 (apoptosis)。然而,三氧化二砷 (ATO, 20 M)刺激細胞也會誘導JNK磷酸化 c-Jun 的N端,進一步誘導 TG-interacting factor (TGIF)/histone deacetylases 1 (HDAC1) 結合在 p21 啟動子Sp1上來抑制p21的表現,來拮抗 ATO 所誘發的細胞死亡。首先,我們針對在三氧化二砷 (20 M) 的刺激之下, ROS 與 c-Src/EGFR/ERK 訊息傳遞路徑以及細胞死亡的相關性進行研究。我們發現在三氧化二砷的刺激之下,c-Src 可以被活化並磷酸化下游的EGFR-Y845以及 EGFR-Y1173。三氧化二砷所誘導產生的 ROS 可以被 NADPH oxidase 的抑制劑: apocynin,DPI,或是superoxide 的清除劑 tiron 所抑制。我們進一步發現三氧化二砷可以刺激細胞 NADPH oxidase 的活性增加以及 NADPH oxidase subunit p67phox 的表現增加並且從細胞質異位 (translocation) 到細胞膜上。減弱 (knockdown) p67phox 的表現也可以減低三氧化二砷誘導的 ROS 產生。因此,我們推測NADPH oxidase 所產生的超氧化物 (superoxide) 是三氧化二砷所誘導產生ROS的主要來源。相反的,三氧化二砷所誘導NADPH oxidase 活化以及超氧化物的產生可以被 c-Src 的抑制劑 PP1 所抑制,但是不能被 EGFR 抑制劑 PD153035 所抑制。另一方面,與三氧化二砷刺激對細胞作用相似,過度表現 c-Src可以刺激 EGFR-Y845/ERK 的磷酸化, p21 的表現以及抑制細胞生長速度。而此現象可以被 apocynin 或是抑制p67phox 基因的表現所抑制。因此,我們推測NADPH oxidase 參與在三氧化二砷誘導的 Src/EGFR/ERK 訊息傳遞路徑。再者,基於 ATO 所誘導的拮抗作用訊息傳遞的路徑,我們進一步研究三氧化二砷刺激下TGIF在拮抗作用的角色。我們發現低濃度三氧化二砷 (0.2 M) 刺激會促進細胞增殖 (proliferation) 的速度以及TGIF 的表現。低濃度三氧化二砷刺激促進細胞非貼附性生長 (anchorage-independent growth),促進細胞侵襲性偽足 (invadopodia) 結構形成,細胞遷移 (migration) 以及細胞侵襲 (invasion) 的能力以及促進 n-cadherin (CDH2),matrix metalloproteinase 2 (MMP2) 以及降低 e-cadherin (CDH1) 的表現。低濃度三氧化二砷也可以刺激TGIF promoter 的活化,而此現象可以被 PP1 或是減弱p67phox表現而抑制。因此,我們推測Src/NADPH oxidase/EGFR 參與在 ATO 刺激所誘導的細胞死亡或是促進惡性轉變 (malignant transformation) 的訊息傳遞路徑。最後,我們發現過度表現 TGIF 也會促進細胞侵襲性偽足結構形成,細胞遷移以及細胞侵襲的能力。總括來說,我們推測 NADPH oxidase 參與在三氧化二砷 (20 M) 所誘導的細胞生長停止或是細胞死亡中,而且被三氧化二砷所誘導的 c-Src 活化所調控。此外,抑制TGIF 表現可能增加 ATO 在治療上的效果。
英文摘要 Although arsenic is a well-known carcinogen, it has been used in the treatment of acute promyelocytic leukemia (APL) as it induces cell apoptosis in many cancer cell lines. Arsenic induced cell carcinogenesis or apoptosis is dependent on the stimulation dose. Previously, arsenic was shown to induce apoptosis via upregulation of p21WAF1/CIP1 (p21) expression through the c-Src/EGFR/ERK pathway and reactive oxygen species (ROS) generation. However, in arsenic trioxide (ATO, 20 M) stimulation, the N-terminal domain of c-Jun phosphorylation by JNK recruits TG-interacting factor (TGIF)/histone deacetylases 1 (HDAC1) to the Sp1 sites and then represses p21 expression, which could antagonize ATO-induced cellular apoptosis in human keratinocytes. Firstly, we aimed to study the relationships among ROS generation, c-Src/EGFR/ERK signaling and cell apoptosis/arrest induced by ATO (20 M). Our data revealed that EGFR-Y845 and EGFR-Y1173 could be phosphorylated by c-Src in response to ATO. Pretreatment with apocynin, DPI, and tiron could remove ATO-induced ROS production. Furthermore, ATO-induced cytosolic p67phox expression increase and p67phox translocation to the membrane resulted in increased NADPH oxidase activity. Knockdown of p67phox could abolish ATO-induced ROS production. Therefore, we suggest that NADPH oxidase-produced superoxide is a major source of ATO-induced ROS production. Conversely, ATO-induced NADPH oxidase activation and superoxide generation could be inhibited by the c-Src inhibitor PP1, but not by the EGFR inhibitor PD153035. Overexpression of c-Src, as well as treatment with ATO, could stimulate EGFR-Y845/ERK phosphorylation, p21 expression, and growth arrest, which could be attenuated by pretreatment with apocynin or the knockdown of p67phox. We suggest that NADPH oxidase is involved in the ATO-induced c-Src/EGFR/ERK pathway. Secondly, based on the ATO-induced antagonistic signaling pathway, we aimed to study the roles of TGIF in ATO stimulation. We found that low-dose ATO (0.2 M) induced cell proliferation and TGIF expression in various cancer cells. Low-dose ATO stimulation induced anchorage-independent growth, cell invadopodia formation, migration, invasion abilities, induced n-cadherin (CDH2), matrix metalloproteinase 2 (MMP2) and decreased e-cadherin (CDH1) protein expression. In addition, TGIF promoter activity which was induced by low-dose ATO stimulation could be reduced by PP1 pretreatment or knockdown p67phox expression. We suggest that, taken together, the Src/NADPH oxidase/EGFR signaling pathway is involved in ATO-induced cell apoptosis and malignant transformation. Finally, we found that overexpression of TGIF also induced cell invadopodia formation, migration and invasion. Collectively, we suggest that NADPH oxidase is involved in the ATO (20 M)-induced arrest/apoptosis and is regulated by c-Src activation. Moreover, blockage of TGIF expression may enhance the ATO therapy effect.
論文目次 Contents
中文摘要………………………………………………………………………….......Ⅰ
Abstract……………………………………………………………………………....Ⅲ
致謝……………………………………………………………………………………......Ⅴ
Contents……...………………………………….………………………………..Ⅵ
Abbreviations……………………………………………………………………..Ⅶ
List of Figures………………………………………………………………….Ⅸ
List of Appendices………………………………………………………….Ⅺ
Introduction……………………………………………………….........1
Materials…………………………………………………………..........12
Methods…………………………………………………………………………......23
Results………………………………….....................31
Discussion………………………………………………………………………....40
Conclution…………………………………………………………...…………….51
References………………………………………………………………………....52
Figures…………………………………………………………………………......63
Appendices……………………………………………………………….……....99
Publications……………………………………………………………………..106
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