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研究生:鄒瑞煌
研究生(外文):Ruey-Hwang Chou
論文名稱:亞砷酸鈉在含人類乳突病毒E6及E7致癌基因之人類癌細胞的細胞毒性機制研究
論文名稱(外文):The Cytotoxic Effects of Sodium Arsenite in Human Papillomaviruses E6 and E7 Oncogenes -Containing Human Cancer Cells
指導教授:黃海美
指導教授(外文):Haimei Huang
學位類別:博士
校院名稱:國立清華大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:106
中文關鍵詞:亞砷酸鈉人類乳突病毒E6蛋白質p53蛋白質E7蛋白質Rb蛋白質程序性凋亡蛋白質激活酵素A
外文關鍵詞:sodium arsenitehuman papillomavirusesE6p53E7Rbapoptosisprotein kinase A
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  • 收藏至我的研究室書目清單書目收藏:2
砷化合物是常見的天然產生物。研究顯示,砷化合物是人類的致癌物質,和肺癌、膀胱癌、皮膚癌、肝癌、腎臟癌及前列腺癌的產生有關。然而,砷化物被用在治療上已有超過2400年的歷史,最近三氧化二砷被廣泛用於治療急性前骨髓淋巴癌(APL),美國食品及藥物管理局(FDA)已於西元2000年9月核准三氧化二砷為急性前骨髓淋巴癌的合法用藥。
子宮頸癌高居婦女癌症死亡原因的第二位。超過百分之九十的子宮頸癌細胞被不同型的人類乳突病毒(HPV)感染,而這些細胞大多擁有正常的p53和Rb兩種抑癌基因。但是,在這些子宮頸癌細胞裡,正常的p53及Rb功能分別被人類乳突病毒的E6及E7致癌基因所抑制,因此,藉由破壞p53/E6或是Rb/E7間的作用途徑是蠻有潛力的治療子宮頸癌策略。這篇論文主要是研究亞砷酸鈉對人類乳突病毒E6和E7致癌基因的影響,亞砷酸鈉對於細胞程序性凋亡(Apoptosis)的影響,並研究亞砷酸鈉毒殺人類乳突病毒感染的子宮頸癌細胞的可能機制。
人類的類淋巴母細胞(TK6)和它的E6轉殖細胞(TK6-E6)以及原本就被16型HPV感染的人類子宮頸癌細胞(SiHa)是本實驗所使用的兩個系統。在人類的類淋巴母細胞方面,亞砷酸鈉能減少TK6-E6細胞的E6致癌基因轉錄,並誘導p53抑癌蛋白和它下游的p21及MDM2蛋白質的表現,然而X-射線則無此作用。與TK6細胞相較,亞砷酸鈉會增加TK6-E6細胞程序性凋亡的反應,包括產生較多的sub-G1比例、較多活化態的caspase-3(17 kD)以及較多的DNA ladder。根據MTT分析的結果得知:與TK6細胞相較,TK6-E6細胞對亞砷酸鈉較為敏感,但對X-射線則較不敏感。這意味著將來在治療有E6感染的癌細胞時,亞砷酸鈉也許可取代游離輻射而達到較好治療效果。
在人類子宮頸癌細胞方面,亞砷酸鈉會抑制HPV E6及E7致癌基因的轉錄,恢復正常p53抑癌基因的功能並誘導Rb蛋白質的表現。在亞砷酸鈉恢復p53基因功能的同時,也伴隨著細胞週期停滯在G2/M期以及細胞程序性凋亡現象的產生。轉殖dominant-negative p53基因至子宮頸癌細胞中,以抑制亞砷酸鈉所誘導正常p53的功能,顯箸地減少細胞程序性凋亡現象。這結果顯示亞砷酸鈉會藉由活化p53居間的途徑而造成子宮頸癌細胞的程序性凋亡。
除了p53之外,還有一些會被HPV E6蛋白分解的分子,例如:Bak和Myc,參與細胞程序性凋亡的調控。據研究指出,Bak蛋白質會被E6蛋白質的C端結合。蛋白質激活酵素A(cAMP-dependent protein kinase A 或PKA)能藉由磷酸化E6蛋白質C端區域上的第156個threonine而抑制它的功能,而此區域不參與E6蛋白質結合和分解p53蛋白質。在本論文中,我主要是研究PKA在調控亞砷酸鈉所誘導的程序性凋亡中所扮演的角色。前處理PKA的抑制劑(HA1004)顯著地減少亞砷酸鈉對SiHa細胞和TK6-E6細胞(皆有E6基因)所造成的細胞程序性凋亡現象,但是HA1004對於TK6細胞(沒有E6基因)則無此作用。這意味著PKA在調控E6蛋白質參與亞砷酸鈉所誘導的程序性凋亡上扮演著重要角色。此外,只有在SiHa細胞和TK6-E6細胞(皆有E6基因)前處理HA1004可以減少亞砷酸鈉所誘導的Bak蛋白質表現,而在TK6細胞(沒有E6基因)則無此現象。然而,在前述的三種細胞中,HA1004對於亞砷酸鈉所誘導的p53蛋白質均無作用。這些結果顯示:在含有E6的癌細胞中,PKA能抑制E6蛋白質去分解亞砷酸鈉所誘導的Bak蛋白質的能力,進而影響細胞程序性凋亡現象,而PKA並不能抑制E6蛋白質去分解亞砷酸鈉所誘導的p53蛋白質的功能。
根據以上的研究結果,亞砷酸鈉在含有HPV的癌細胞中會誘導細胞程序性凋亡現象可能的原因為:(1)抑制E6和E7兩致癌基因表現,(2)恢復癌細胞的p53抑癌基因功能,以及(3)有部分是PKA參與抑制E6蛋白質去分解Bak蛋白質的能力。

Arsenic compounds are common, naturally occurring substances. They have been reported to be human carcinogens associated with malignancies of the lung, bladder, skin, liver, kidney, and prostate. However, arsenic compounds have been used as therapeutic agents for more than 2,400 years. Recently, arsenic trioxide (As2O3) was wildly used to cure acute promyelocytic leukemia (APL). The Food and Drug Administration (FDA) of the USA has approved arsenic trioxide for the treatment of APL in September 2000.
Cervical cancer is the second leading cause of death from cancer in women worldwide. Over 90% of human cervical cancer cells are infected with different types of human papillomaviruses (HPVs) and possess wild type p53 and Rb tumor suppressor genes. But in these cells, normal p53 and Rb functions are abolished by HPVs E6 and E7 oncogenes, respectively. Therefore, restoration of p53 or Rb function by blocking E6/p53 or E7/Rb pathway might be a potential therapeutic purpose for these cancer cells. In the present study, we investigated the effects of sodium arsenite (SA) on HPVs E6 and E7 oncogenes, the effects of SA on apoptotic responses, and try to promote SA as a potential therapeutic agent for HPV-positive cancer cells.
Two systems were used in this study: (1) the human lymphoblastoid cells (TK6 cells), and their E6-transfectants (TK6-E6 cells), (2) the human cervical carcinoma cells originally infected with HPV-16 (SiHa cells). Treatment with SA, but not X-ray, decreased the E6 mRNA levels and induced the expressions of p53, and its down stream genes, p21, and mdm2 in TK6-E6 cells. SA enhanced apoptotic responses, including more sub-G1 percentages, more activated caspase-3 fragments (17 kD), and more DNA ladder in TK6-E6 cells than these in their parental TK6 cells. According to the results from MTT assay, TK6-E6 cells were more sensitive to SA, but more resistant to ionizing radiation (IR) than TK6 cells. It implied that instead of IR, SA could be a potential therapeutic agent for E6-possitive cancer cells.
In human cervical cancer cells, SA down-regulated E6 and E7 mRNA levels, restored p53 tumor suppressor pathway, and induced Rb expression. While SA restored normal p53 function, G2/M arrest in the cell cycle progression and apoptosis occurred. Transfection of a dominant-negative p53 markedly reduced the SA-induced apoptosis, indicating that p53 mediated SA-induced apoptosis in SiHa cells.
Besides p53, other molecules are involved in regulation of apoptosis. Cyclic AMP-dependent protein kinase A (PKA) has been reported to inhibit E6 function by phosphorylation of threonine residue at its C-terminal region, which is not involved in p53 binding and degradation. But, E6 binds to Bak, an apoptosis inducer, at this region. In this study, I investigated the roles of PKA in regulation of SA-induced apoptosis. Pretreatment with a PKA inhibitor, HA1004, significantly reduced the SA-induced apoptotic cell death in E6-positive SiHa and TK6-E6 cells, but not in E6-negative TK6 cells. It implied that PKA played some roles in regulation of E6 function, which was involved in SA-induced apoptosis, in E6-positive cancer cells. Furthermore, pretreatment with HA1004 decreased SA-induced Bak expression only in E6-possitive cancer cells. However, HA1004 did not affect SA-induced p53 expression in both E6-positive and E6-negative cancer cells. These results suggested that PKA inhibited E6 degrading SA-induced Bak, and resulted in apoptotic cell death in E6-positive cancer cells, but PKA could not inhibit the E6 function of degradation of SA-induced p53.
Base on these above results, SA-induced apoptotic cell death in HPV-positive cancer cells might result from the following: (1) down regulation of E6 and E7 oncogenes, (2) restoration of the p53 tumor suppressor pathway, and (3) at least in part, involvement of PKA in inhibition of Bak degradation by E6.

Contents
Contents …………………………………………………………….………… 1
Publication List and Conferences …………………………………………... 5
Abbreviations ………………………………………………….……………... 6
中文摘要 ……………………………………………………………………..… 7
Abstract ……………………………………………………………………..… 9
Chapter 1
Background
1.1 Arsenic Compounds ...……………………………………………... 11
1.2 The Possible Modes of Action of Arsenic Carcinogenesis …...….… 11
1.3 Arsenic compounds in Therapy ……………………………………. 15
1.4 Possible Mechanisms of Action of Arsenic Trioxide (As2O3) in Cancer Treatment ……………………………………………….……..….... 16
1.5 Human Papillomaviruses (HPVs) ……………………………….… 18
1.6 The HPVs E6 oncoproteins ……………………………………...… 18
1.7 The HPVs E7 oncoproteins ………………………………………... 26
1.8 Cyclic-AMP Dependent Protein Kinase (PKA) ………..……………. 26
1.9 Specific Aims ……………………………………………………..... 28
Chapter 2
Sodium Arsenite Suppresses Human Papillomavirus-16 E6 Gene and Enhances Apoptosis in E6-Transfected Human Lymphoblastoid Cells
2.1 Abstract …………………………………………………………….. 29
2.2 Introduction ………………………………………………………… 30
2.3 Materials and Methods
Materials ……………………………………………………...…….. 32
Cells and Culture Conditions ……………………………………….. 32
Transfection of HPV16-E6 Gene ……………………………………... 32
Western Blotting …………………………………………………….. 33
Genomic DNA Extraction and Polymerase Chain Reaction (PCR) .... 33
RNA Extraction and Reverse Transcription Polymerase Chain Reaction (RT-PCR) …………………………………………………….………. 34
DNA Analysis by Flow Cytometry …………………………….…….. 35
DNA Fragmentation Assay ……………………………………….….. 35
MTT Assay ……………………………………………………….…... 35
2.4 Results
Selection of Neo and E6 Transfected Clones ………………….……... 37
HPV16 E6 mRNA Levels were Down Regulated by SA ………….... 37
SA Altered p53, p21waf1/cip1 and MDM2 Protein Levels ………………... 37
SA Enhanced Apoptotic Responses in E6-Transfected TK6 Cells .….. 38
E6-Transfected TK6 Cells were More Sensitive to SA, but More Resistant to IR ………………….……………………………………….…...…… 39
2.5 Discussion
The Possible Reasons Why TK6-E6 Cells Were More Sensitive to SA than TK6 Cells …………………………………………………………….… 40
The Possible Reasons Why p53 Proteins Were Induced by SA in E6-Transfected TK6 Cells …………… ……………………………… 40
Potential Therapeutic Roles of Arsenite in HPV-positive Cancer Cells ….. 41
Conclusions ………………………………………………………………. 42
2.6 Tables ……………….. …………………………………………………… 43
2.7 Figures . …………………………………………………………………... 44
Chapter 3
Restoration of p53 Tumor Suppressor Pathway in Human Cervical Carcinoma Cells by Sodium Arsenite
3.1 Abstract …………………………………. ………………………………. 50
3.2 Introduction ………………………………………………………… …… 51
3.3 Materials and Methods
Materials …………….…….. ……………………………………………. 53
Cells and Culture Conditions …………………………… ………………. 53
RNA Extraction and Reverse Transcription Polymerase Chain Reaction (RT-PCR) …………. …………………………………………………… 53
Western Blotting ………………………………………………………... 54
Immuno-Fluorescence Staining of Cellular p53 ……………………….. 54
Flow Cytometric Analysis ……………………………………………… 54
Dual-Parameter Flow Cytometric Analysis of Normal, Apoptotic, and Necrotic Cells ………………………………………………………… 54
Apoptotic Cells Staining ……….. ……………………………………….. 54
DNA Fragmentation Assay …………………………………………….. 55
Plasmid Construction and Transfection ………………………………….. 55
3.4 Results
HPV-16 E6 mRNA Levels Were Down-Regulated by SA, but not by IR
…………………………………………………………………………. 56
SA Activated The p53 Tumor Suppressor Pathway and Caused p53 Accumulation in Cellular Nuclei ……………………………………….. 56
SA Suppressed HPV-16 E7 Oncogene and Induced Rb Expression …… 56
SA Blocked The Cell Cycle Progression in G2/M Phase Coinciding with Decreased Cdc25A and Cyclins ………………………………………... 57
Induction of Apoptosis Was The Major Event after SA Treatment … …… 57
Expression of Dominant-Negative p53 Significantly Rescued SiHa Cells from SA-Induced Apoptotic Cell Death ………………………………... 58
3.5 Discussion ……………………………………………………………. 59
Other Similar Researches ………………………………………………... 59
The Possible Reasons Why p53 Function Was Restored by SA in SiHa Cells
…………………………………………………………………………... 59
The Possible Reasons Why SA Induced G2/M Arrest in SiHa Cells .. …...60
The Possible Reasons Why SA Induced Apoptotic Responses in SiHa Cells
………………………… ……………………………………………….. 60
Conclusions ………………………………. ……………………………... 61
3.6 Tables …………………………………………………………………….. 62
3.7 Figures …………………………………………………………….……. 65
Chapter 4
Involvement of cAMP-Dependent Protein Kinase (PKA) in Arsenite-Induced Apoptosis in E6-Positive Cancer Cells
4.1 Abstract …………. …………………………………………………….. 70
4.2 Introduction ……………………… ……………………………………. 71
4.3 Materials and Methods
Materials ………………………………………………………………... 73
Cells and Culture Conditions ………………………………………… 73
Dual-Parameter Flow Cytometric Analysis of Normal, Apoptotic, and Necrotic Cells ………………………………………………………… 73
Western Blotting …………………………………………………….. 73
4.4 Results
PKA Inhibitor, HA 1004, Protected E6-Positive Cancer Cells from SA-Induced Apoptotic Cell Death. …………………………………….. 74
HA1004 Reduced SA-Induced Bak Expression, but Had No Effect on SA-Induced p53 Expression in E6-Positive Cancer Cells. ………………. 74
4.5 Discussion
PKA and Apoptosis …………………………………………………... 76
The Possible Relationship Among E6, Bak, and Apoptosis ……………. 76
Conclusions …………………………………………………………… 77
4.6 Figures ……………………………….. ………………….………...… 78
Chapter 5
Conclusions and Perspectives
5.1 Conclusions …………………………………...………...…………… 81
5.2 Perspectives ……………………………………………...…………... 82
5.3 References …………………………………...………………………. 83

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