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系統識別號 U0026-2408201022205000
論文名稱(中文) 慢性暴露在低劑量的三氧化二砷誘發人類角質上皮細胞的癌化
論文名稱(英文) Chronic exposure to low-level ATO induces oncogenic phenotype in HaCaT cells
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 98
學期 2
出版年 99
研究生(中文) 洪小凡
研究生(英文) Xiao-Fan Hung
學號 t3697408
學位類別 碩士
語文別 英文
論文頁數 57頁
口試委員 指導教授-黃暉升
口試委員-俞松良
口試委員-陳昌熙
中文關鍵字 慢性  三氧化二砷  癌化 
英文關鍵字 chronic  arsenic trioxide  carcinogenesis 
學科別分類
中文摘要 有機砷及無機砷廣泛的存在於自然環境中。流行病學指出,慢性的暴露在含砷的環境下,罹患皮膚、肺、肝和泌尿道等癌症的風險會大大的提高。然而,砷化物用於疾病上的治療已有兩千四百年的歷史了,尤其是---三氧化二砷(As2O3, ATO),可有效的治療急性前骨髓性白血病,此外,三氧化二砷也被用來作為固態腫瘤的治療。基於有效並安全的應用砷化物在人體疾病的治療,其本身的致癌及治癌的機轉是需要被完整的研究的。根據我們過去的研究發現,在人類的角質上皮細胞中,低劑量的三氧化二砷增加了細胞生長,而高劑量則促進細胞的死亡。為了更進一步的探討三氧化二砷致癌的機轉,我們將已轉型的人類角質上皮細胞株(HaCaT) 長期的培養在含低劑量的三氧化二砷培養液中。實驗結果發現,慢性的暴露在低劑量的三氧化二砷使得細胞的增生、爬行作用和侵犯作用顯著的增加了。我們更進一步的去探討其可能發生的作用機轉,結果顯示,在慢性的暴露三氧化二砷的細胞中,MMP-9、ROS、TGIF和 p-EGFR(Y845)的表現也隨之增多。此外,三氧化二砷所造成的細胞爬行增加的現象,有MMPs、Superoxide以及TGIF的參與。在訊息傳遞的調控方面,我們發現TGIF和 p-EGFR(Y845)的表現是有關聯性的。另一方面,我們移除了長期培養在三氧化二砷之細胞的砷刺激,兩個星期後,發現其細胞存活狀態、爬行和EGFR磷酸化的表現並沒有回歸到控制組的狀態。這表示,慢性的暴露在低劑量的三氧化二砷中,可能會對細胞的生理功能上造成不可逆的轉變。此外,三氧化二砷所造成的細胞癌化現象除了在HaCaT中有觀察到之外,癌細胞可能也會受其影響。我們發現,人類乳癌細胞株(MCF-7)和肝癌細胞株(Huh-7)在受到長期低劑量的三氧化二砷暴露後,其細胞的生長也加速了,並且觀察到MCF-7的細胞爬行增加。總而言之,本篇對於三氧化二砷致癌機轉的了解,可能將有助於臨床上使用三氧化二砷做為疾病的治療之應用。
英文摘要 Arsenic existed ubiquitously in the environment in both inorganic and organic forms. Epidemiological studies had identified an increased risk of various tumors, including those of the skin, lung, liver and urinary tract, when chronic exposure to arsenic. However, arsenic had also been used to treat a number of diseases for more than 2400 years. Especially, arsenic trioxide (ATO) can be effectively used to treat acute promyelocytic leukemia, and some other solid tumors. The mechanisms of the carcinogenic and therapeutic effects of arsenic were still poorly understood, and should be further elucidated for therapeutic purposes. Previously, we found that low-level ATO increased cellular proliferation, while high-level ATO induced cellular toxicity in keratinocytes. To further investigate the role of low-level ATO in the carcinogenesis, we exposure HaCaT (transformed human keratinocyte cell line) cells with low-level ATO for a long period. We found that chronic treatment with low-level ATO to HaCaT could increase cellular proliferation, migration, invasion, MMP-9, ROS, TGIF, and p-EGFR(Y845) expression. Moreover, cells migration ability was largely reduced after inhibit MMPs, superoxide, and TGIF in long-term ATO exposure cells. Besides, TGIF was involved in arsenic trioxide-induced p-EGFR(Y845) expression. On the other hand, interruption of ATO supply in long-term ATO exposure cells did not restore cell viability, cell migration and phosphorylation of EGFR to control cells level, it might because cells signaling were irreversibly altered after long-term of ATO exposure. In addition, low dose ATO exposure also affected breast cancer cell (MCF-7) and hepatoma cell line (Huh-7) proliferation and increased MCF-7 cell migration ability, indicated that chronic low dose exposure of ATO might have carcinogenic effect not only in keratinocytes but also in breast cancer cells, and hepatoma cells. Overall, in this study, the mechanisms that involved in arsenic trioxide induced-carcinogenesis might give us hints in clinical application.
論文目次 Index
Abstract in Chinese………………………………………………I
Abstract in English………………………………………………II
Acknowledgement…………………………………………………………III
Contents……………………………………………………………………………V
List of Figures…………………………………………………………VI
List of Appendix………………………………………………………VII
List of Abbreviations…………………………………………VIII
List of Reagents………………………………………………………X
Contents
Introduction…………………………………………………………………1
Hypothesis………………………………………………………………………8
Materials and Methods…………………………………………10
Results………………………………………………………………………………19
Figures………………………………………………………………………………26
Discussion………………………………………………………………………40
Appendix……………………………………………………………………………45
References………………………………………………………………………50
List of Figures
Figure 1. Opposing effects of arsenic trioxide on cell proliferation
………………………………………………………………………26
Figure 2. Arsenic trioxide significantly increased cell proliferation, migration, and invasion in ATO (0.1 microM) cells versus control cells
………………………………………………………………………27
Figure 3. Interruption of arsenic trioxide supply did not restore cell viability, migration, and p-EGFR(Y845) expression to control cells level
………………………………………………………………………30
Figure 4. After long-term of arsenic trioxide treatment, MMP-9 expression was increased and cell migration was related to MMPs expression
………………………………………………………………………32
Figure 5. Chronic exposure to arsenic trioxide induced ROS expression, and cell migration
………………………………………………………………………33
Figure 6. Chronic exposure to low-dose arsenic trioxide increased phosphorylation of EGFR (Y845), which might be regulated by MMPs
………………………………………………………………………35
Figure 7. Arsenic trioxide-increased TGIF expression was involved in migration of HaCaT
………………………………………………………………………36
Figure 8. Chronic exposure to arsenic trioxide increased phosphorylated EGFR(Y845) via TGIF
………………………………………………………………………37
Figure 9. Long-term of arsenic trioxide treatment increased cell proliferation in MCF-7, as well as Huh-7, and cell migration was accelerated in MCF-7 cell line
………………………………………………………………………38
Figure 10. Arsenic trioxide did not alter anchorage-independent cell growth in HaCaT, MCF-7, and Huh-7
………………………………………………………………………39
List of Appendix
Appendix 1. Arsenic trioxide targets multiple cellular pathways
………………………………………………………………………45
Appendix 2. The hallmarks of cancer
………………………………………………………………………46
Appendix 3. EGFR activation and signaling in cancer cells
………………………………………………………………………47
Appendix 4. MMPs: the regulators of the tumor microenvironment
………………………………………………………………………48
Appendix 5. Oxidative level-mediated cell physiology
………………………………………………………………………49
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