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系統識別號 U0026-3001201313484600
論文名稱(中文) Aurora-A的活化參與低濃度砷誘發角質細胞有絲分裂異常與癌化
論文名稱(英文) Aurora-A overexpression contributes to low concentration of arsenic-induced aberrant mitosis and tumorigenesis in 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) 吳金漢
研究生(英文) Chin-Han Wu
學號 s58931188
學位類別 博士
語文別 英文
論文頁數 84頁
口試委員 指導教授-劉校生
指導教授-許漢銘
口試委員-王應然
口試委員-郭浩然
口試委員-蔡志仁
口試委員-李志宏
中文關鍵字 Aurora-A    角質細胞  有絲分裂 
英文關鍵字 Aurora-A  arsenic  keratinocyte  mitosis 
學科別分類
中文摘要 第一部分
砷廣泛分佈於大自然環境中,是一種具有雙面性質的類金屬化合物。高濃度的砷可用來治療疾病,包括急性前骨髓性白血病、癌症等。觀察顯示,長時間暴露在低劑量砷的環境中會促進細胞增殖和導致癌變。中心體的倍增是造成染色體不穩定的重要原因之一,且經常在癌細胞中被發現。Aurora-A蛋白是有絲分裂激酶,過度的表現Aurora-A蛋白會導致中心體倍增和不穩定。我們先前的研究顯示低濃度的砷會誘導永生型膀胱細胞中Aurora-A的過度表達。因此,我們推測,低濃度的砷引起的異常有絲分裂與Aurora-A的過度表達可能相關。透過反轉錄聚合酶連鎖反應實驗、西方墨點法、免疫組織化學染色與免疫螢光染色,我們發現Aurora-A的mRNA與蛋白質在台灣砷中毒地區的波文氏病(As-BD)與鱗狀細胞癌(As-SCC)檢體中表現增加。相似的結果也在低濃度砷處理過的角質細胞株(HaCaT cells)發現。透過顯微鏡觀察,我們發現砷處理過後角質細胞有異常的有絲分裂、倍增的中心體與多核細胞的產生,這些現象可能與Aurora-A蛋白的增加有關。我們進一步透過染色體免疫沉澱,啟動子活性與小分子干擾RNA檢測等實驗,證明砷誘發的轉錄因子(E2F1)會直接轉錄調控Aurora-A的表現。最後,在砷處理的角質細胞和As-BD,變異型p53與Aurora-A的增加可能有關連性。

第二部分
SR-T100是從台灣特有種黃水茄萃取出來的水溶性藥物,solamargine為其主要有效成分。透過細胞實驗,SR-T100可透過活化細胞凋亡機制抑制腫瘤細胞生長。動物實驗也同樣發現當UVB誘發的皮膚腫瘤在塗抹SR-T100凝膠後可誘發細胞凋亡機制,治療皮膚瘤瘤。而預先處理一個月低濃度砷的角質細胞對SR-T100有較高的感受性。此外,角質細胞不論是否經過低濃度砷預先處理,細胞Aurora-A 蛋白的表現在SR-T100暴露18小時後皆大量下降。

總結
我們的研究發現低濃度砷會誘發E2F1-Aurora-A路徑過度活化與造成角質細胞異常有絲分裂。過度表現Aurora-A蛋白可能透過協同作用與異常的p53進一步引發皮膚腫瘤的形成。而預先經砷處理後的角質細胞對抗癌藥物SR-T100較敏感,是否與細胞週期基因的變化(包含Aurora-A)有關值得進一步觀察。我們的研究結果顯示,Aurora-A在砷相關癌症的預防與治療上,可能是一個潛在的標的。
英文摘要 Part I
Arsenic is a dual metalloid compound that is widely distributed in the environment. High concentration of arsenic has been effectively used to treat many ailments, including acute promyelocytic leukemia and solid tumors. However, chronic exposure to low concentration of arsenic promotes cell proliferation and carcinogenesis both in vitro and in vivo. Centrosome amplification, the major cause of chromosome instability, occurs frequently in cancers. Aurora-A is a mitotic kinase, overexpression of Aurora-A causes centrosome amplification and instability. Our previous study revealed that low concentration of arsenic induces Aurora-A overexpression in immortalized bladder cells. Therefore, we hypothesized that low concentration of arsenic-induced aberrant mitosis is associated with Aurora-A overexpression. The mRNA and protein levels of Aurora-A were increased in immortalized keratinocyte HaCaT cells after low concentration (<1M) of arsenic treatment as well as in Bowen’s disease (BD) and squamous cell carcinoma (SCC) from arseniasis-endemic areas in Taiwan by reverse transcription-PCR, Western blotting, immunohistochemistry, and immunofluorescence staining. Aberrant spindles, multiple centrosomes and multinucleated cells were detected under fluorescence microscopy in HaCaT cells after arsenic treatment, which is associated with increased expression and activity of Aurora-A. We further revealed that Aurora-A was regulated by arsenic-induced transcriptional factor E2F1 demonstrated by chromosome immunoprecipitation, promoter activity and small interfering RNA assays. Finally, in arsenic-treated HaCaT cells and in BD, a significant increase of dysfunctional p53 was found to be correlated with an increase of Aurora-A.

Part II
SR-T100 is a new patented water-soluble product extracted from Solanum incanum. Water-soluble solamargine is the main active components of SR-T100. In this study we have demonstrated the mechanisms of SR-T100 in killing SCCs in cancer cell lines (A431, SCC-4, -9, 25) and UVB-induced SCC of hairless mice. Interestingly, arsenic pre-treated HaCaT cell becomes sensitive to SR-T100 and the protein level of Aurora-A is decreased after SR-T100 treatment for additional 18h.

Conclusion
Altogether, our data suggest that low concentration of arsenic induces activation of E2F1-Aurora-A axis and results in aberrant mitosis of keratinocytes. Overexpression of Aurora-A and dysfunctional p53 may act synergistically to trigger further skin tumor formation. In addition, it is interesting to investigate whether the anticancer mechanism of SR-T100 is Aurora-A related. Our findings suggest that Aurora-A may be a potential target for the prevention and treatment of arsenic-related cancers.
論文目次 中文摘要..........................................................................................................Ⅰ
Abstract...........................................................................................................Ⅲ
致謝.................................................................................................................Ⅴ
Contents………………..………………………………………………….….….....Ⅵ
Abbreviations list……..…………………….………………………………..……..Ⅹ
Chapter 1: Introduction
Part Ⅰ: The role of Aurora-A in arsenic carcinogenesis
1-1 Introduction of Arsenic…………………………………………………….…..2
1-2 Mechanism of arsenic-induced carcinogenesis…………………………….3
1-3 Arsenic carcinogenesis and cell cycle regulation………………...………...5
1-4 Arsenic and chromosome aberration……………………………….………..6
1-5 Mechanism of chromosome aberration………………………….…………..6
1-6 The role of Aurora kinase in tumorigenesis……………………………........8
1-7 The regulated mechanism of Aurora-A in arsenic-related tumoregenesis.9
1-8 The relationship between Aurora-A and p53……………………………….10
Part Ⅱ : The novel medicine in skin cancer therapy
1-9 Introduction of skin cancers……………………………………………...…..11
1-10 The clinical therapy of skin cancer……………………………………..…..11
1-11 Introduction of Solanum incanum……………………..…………………...12
1-12 The anticancer effect of solamargine……………………………………...13
1-13 Aurora-A as anticancer target……………………………..………………..13
1-14 Specific aims and study designs…………………………………..………14

Chapter 2: Materials and Methods
Part I
2-1 Reverse transcriptional polymerase chain reaction (RT-PCR)................16
2-2 Immunohistochemistry (IHC) staining…………………………….………..16
2-3 Cell line and treatment………………………………..……………………...17
2-4 Flow cytometry analysis……………………………………..……………....18
2-5 Bromodeoxyuridine(5-bromo-2'-deoxyuridine, BrdU) staining…………...18
2-6 Western blot analysis……………………….………………………….…....18
2-7 Immunofluorescent assay…………………………………………….……..19
2-8 In vitro DNA methylation (IVD)……………………………………………...19
2-9 Bisulfite-sequencing PCR………………………………………..………….20
2-10 Real-Time PCR……………………………………………………………...20
2-11 Promoter activity assay…………………………………………..………...21
2-12 Chromatin Immunoprecipitation (ChIP) assay…………………………...22
2-13 Suppression of E2F1 by shRNA……………………………………….….22
2-14 Statistical analysis…………………………………………..………..…….23
Part II
2-15 Materials and cell lines………………………………………....……..…...23
2-16 Cell viability assay……………………………………………..……….…..24
2-17 Western blotting, immunofluorescence and DNA fragmentation analysis…………………………………………………………………………….24
2-18 Narrowband UVB irradiation, SCC formation on mouse skin and SR-T100 gel topical treatment……………………………………………………………...25
2-19 Immunohistochemistry………………………………………………..…...26

Chapter 3: Results
Part I
3-1 Aurora-A expression in arsenic-related skin cancers..............................28
3-2 Effect of low concentration of arsenic on cell viability and cell cycle…...28
3-3 Effect of low concentration of arsenic on Aurora-A expression………....29
3-4 Morphological alteration and aberrant distribution of Aurora-A in arsenic-treated HaCaT cells.........................................................................30
3-5 Promoter methylation and gene amplification of Aurora-A in arsenic-treated HaCaT cells..................................................................................................31
3-6 Aurora-A was transcriptionally up-regulated by E2F1 after arsenic treatment…………………………………………………………………………..32
3-7 Increased expression of p53 in arsenic-treated cells and skin cancers.33
Part II
3-8 Dose and time dependency of SR-T100-induced cancer cell apoptosi..34
3.9. SR-T100 induces apoptotic signal cascades in cancer cells.................34
3-10 Efficacy and toxicity of SR-T100 gel on UVB-induced mouse SCC.....35
3-11Expression of apoptosis-associated markers of mouse cutaneous SCC following intralesional injection of SR-T100 solution....................................35
3-12 SR-T100-induced cytotoxic effect in arsenic-treated HaCaT cells.......36
3-13 The expression of Aurora-A in arsenic-treated HaCaT cells after SR-T100
treatment......................................................................................................36

Chapter 4: Discussion and Conclusion....................................................................................................38
References...................................................................................................46

Tables and Figures
Table 1 Basic data of the BD and SCC patients………………………………55
Table 2 The primer sets used in bisulfite-sequencing PCR……………….....56
Table 3 The annealing temperatures used for different sets of primers in bisulfite- sequencing PCR……………………………..……………………......57
Table 4 The expression levels of Aurora-A in BD and SCC………………….58
Table 5 The expression levels of p53 in BD and SCC………………………..59
Figure 1 Aurora-A mRNA expression in arsenic-related skin cancers..........60
Figure 2 Aurora-A protein expression in arsenic-related skin cancers.........61
Figure 3 Low concentration of arsenic promotes cell proliferation……........62
Figure 4 Low concentration of arsenic increases Aurora expression...........64
Figure 5 Arsenic-induced multinucleated giant cell and abnormal chromosomal segregation..................................................................................................65
Figure 6 Arsenic-induced multiple centrosome formation was related to Aurora-A overexpression.............................................................................66
Figure 7 Neither promoter methylation nor genomic amplification altered Aurora-A expression after arsenic treatment...............................................68
Figure 8 Aurora-A activation was related to E2F1 expression.....................70
Figure 9 Aurora-A was transcriptionally regulated by E2F1………………....72
Figure 10 Overexpression of dysfunctional p53 is involved in arsenic-induced tumor progression………………………………………………………………..74
Figure 11 The relationship between Aurora-A and p53……………………....75
Figure 12 Dose- and time-dependent inhibition of cell viability by SR-T100…….……………………………………………………………………..76
Figure 13 SR-T100 upregulates protein expression responsible for apoptosis in A431 and SCCs cells……………………………………..…………………...78
Figure 14 Therapeutic effects of SR-T100 gel on UVB-induced papillomas and MISCCs (microinvasive squamous cell carcinoma) in hairless mice……….79
Figure 15 Expression of the apoptotic markers of mouse cutaneous SCC after intralesional injection of SR-T100 solution…………………………………….81
Figure 16 Dose-dependent inhibition of cell viability by SR-T100 in arsenic treated HaCaT cells……………………………………………….……………..82
Figure 17 The protein level of Aurora-A in cells after SR-T100 treatment….83
Figure 18 The hypothetical mechanism of arsenic-induced Aurora-A activation and skin tumorigenesis…………………………………………..……………...84
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