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研究生:許耿福
研究生(外文):Keng-fu Hsu
論文名稱:扁平細胞癌抗原在子宮頸癌上功能及基因治療的研究
論文名稱(外文):The function of squamous cell carcinoma antigens and role of gene therapy in uterine cervical cancer
指導教授:蕭璦莉周振陽周振陽引用關係
指導教授(外文):Ai-Li ShiauCheng-yang Chou
學位類別:博士
校院名稱:國立成功大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:英文
論文頁數:96
中文關鍵詞:扁平性上皮細胞癌抗原apoptosis子宮頸癌癌症基因治療autophagyoncolytic virus溶解體
外文關鍵詞:lysosomeautophagyapoptosisoncolytic viruscancer gene therapycervical cancersquamous cell carcinoma antigen (SCC A)cathepsin
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中文摘要
子宮頸癌為台灣地區婦女癌症主要死亡原因之一。臨床上,我們用血清中扁平性上皮細胞癌抗原(SCC A)作為腫瘤標誌來做為預測子宮頸癌病人的預後及追蹤病人的病情。雖然由基因序列分析得知,SCC A 有SCC A1及SCC A2兩個基因存在,但是對SCC A在子宮頸上皮細胞癌化所扮演的角色以及可能做為基因治療的標的並不是非常的清楚。在本論文中,我們嘗試探討兩個SCC A在子宮頸癌角色的問題。第一、到底在子宮頸癌組織中, SCC A1及SCC A2何者表現量高?其所代表的臨床意義為何?若是癌細胞中SCC A表現比正常上皮高出甚多,據此是否可以做為臨床子宮頸癌基因治療的標的?為回答上面的問題我們取不同癌化程度的子宮上皮組織,直接以雷射微切片的方式,避開其他正常組織,把腫瘤細胞切下來,以同步PCR (real-time PCR)的方法,直接偵測這些異常細胞的SCC A1,SCC A2的表現。我們發現,隨著癌化程度的增加,SCC A2比SCC A1的比值也隨之增加。同時在子宮頸癌病患中SCC A2比SCC A1比值高者,有較不好的預後。因此,我們得知,在子宮頸癌細胞中SCC A2的表現量比SCC A1高,同時有決定病人預後的角色。據此結論,我們clone SCC A2的啟動子,以oncolytic virus 做為載體, 做成新的病毒,Ad-KFH,行子宮頸癌症基因治療實驗。我們發現在小鼠的動物模式實驗中,以SCC A2啟動子做成的腺病毒可以專一有效的控制腫瘤細胞,尤其是再加上cisplatin效果更明顯。其次,到底SCC A1及SCC A2在子宮頸癌細胞中高度表現的生理意義為何?我們首先嘗試用免疫染色做血管密度(microvessel density, MVD)及3D power立體超音波的方法,去探討SCC A與子宮頸癌可能的血管新生的關係。但是,結果發現並沒有一致的相關性。可能的解釋原因為:在子宮頸癌組織血管分佈極為不均勻,無法用MVD分析SCC與血管新生的關係。利用3D power立體超音波由臨床病人當中,我們發現實際的腫瘤血管分佈很不均勻,我們觀察血管分佈,同時把它分成四種不同血管模式。再者,為了解SCC A1/cathepsin L在子宮頸癌拮抗細胞死亡的角色,我們以葡萄醇 (resveratrol, RAV) 為刺激源,結果發現葡萄醇會引起子宮頸癌細胞autophagy 反應及apoptosis.而這些細胞毒性反應是介由溶解體(lysosome)內的酵素釋出至細胞質所至。由於SCC A1為溶解體(lysosome)內的酵素cathepsin L 的抑制劑,我們發現抑制SCC A1表現會增加子宮頸癌細胞死亡,換言之,SCC A1高度表現的結果可以抵抗子宮頸癌細胞在不良環境的死亡。綜合以上研究我們結論:SCC A2的表現在子宮頸癌較高,同時與病人的預後有關; 而SCC A1介由抑制cathepsin L的角色,具有拮抗子宮頸癌癌細胞死亡功能。因此,SCCA1 , SCC A2兩者均可以做為將來癌症治療的標的。
ABSTRACT
Uterine cervical cancer is the major cause of female cancer death worldwide as well as in Taiwan. Clinically, we use squamous cell carcinoma antigen (SCC A) as a serologic tumor marker for patients with squamous cell carcinoma of the cervix. Serum concentrations of this marker correlate well with the disease stage, the presence or absence of risk factors, the effect of treatment, and the course of the disease. The SCC A, formerly referred to as TA-4, was isolated by Kato and Torigue in 1977 from cervical tissue. As revealed by cDNA and genomic cloning analyses, SCC A is encoded by two genes SCC A1 and SCC A2 which are 92% identical and belong to the ov-serpin family. However, the real biological function of the two genes and their possible use as a target for therapy are still unknown. In this study, I have tried to answer two questions: first, what is the relative expression level of SCC A1 and SCC A2 in uterine cervical cancer tissue? If their expression is higher in neoplastic than in normal cell, can they serve as a target for in cancer gene therapy? Secondly, what is the biologic function of SCC A in cervical cancer cells? By using laser microdissection and real-time quantitative PCR procedures, we found that the SCCA2/A1 mRNA ratios were progressively increased from normal, dysplastic, to cancer cells, and the mean ratio was significantly higher in cancer tissues than that in normal uterine epithelium. High SCCA2/SCCA1 mRNA ratios (ratio >1) was an independent predictor of disease recurrence. Patients with high SCCA2/SCCA1 mRNA ratios had a significantly lower 2-year disease-free survival (DFS) than patients with low SCCA2/SCCA1 mRNA ratios. Since SCC A2 is expressed higher in cervical cancer cells, we therefore constructed a recombinant adenovirus under the transcriptional control of the SCCA2 promoter for specific replication in and lysis of SCCA2-producing cervical cancer cells. This oncolytic virus, named Ad-KFH retarded tumor growth and prolonged survival in tumor-bearing mice. Secondly, what is the biological function of SCC A in cervical cancer? For exploring the function of SCC A in cervical cancer, we studied the relationship of angiogenesis and cell death. To determine microvessel density (MVD) in cervical cancer tissue, no correlation of SCC A and MVD could be demonstrated by using the conventional immunohistochemical stain. However, we were able to observe four specific vessel distribution patterns with the use of most updated 3D power Doppler ultrasound in tumor tissue of cervical cancer in vivo. Since SCC A1 an inhibitor of lysosomal protease, cathepsin (cat) L, we investigated if the cat L-SCCA 1 lysosomal pathway and autophagy were involved in cancer cell death. Prolonged treatment with resveratrol (RSV) can induce autophagy responses and apoptotic cell death in cervical cancer cells. This effect is through translocation of cat L from lysosomes to cytosol. Inhibition of SCC A1 through interruption of cat L activity, we found apoptotic cell death were enhanced in cervical cancer cells. In conclusion, we have found that SCC A2 expression level is higher in cervical cancer tissue and patients with high SCCA2/SCCA1 ratio carried poor prognosis; SCC A1 play an anti-apoptotic role through inhibition of lysosomal protease cat L in cervical cancer. Both SCC A1 and SCC A2 may serve as useful targets for cervical cancer therapy.
考試合格證書--------------------------------------2
Contents------------------------------------------3
中文摘要------------------------------------------5
英文摘要------------------------------------------7
誌謝----------------------------------------------8
Table contents------------------------------------10
Figure contents-----------------------------------11
Introduction
1. Squamous cell carcinoma antigens-------------13
2. Conditionally replicating adenoviruses and
caner target therapy-------------------------14
3. Angiogenesis---------------------------------15
4. Autophagy , cathepsins and lysosomal cell
death----------------------------------------16
5. Rationale of this study----------------------17
Material and Methods
1. Human samples collection---------------------18
2. Tissue preparation and laser micodissection
(LMD) ---------------------------------------19
3. DNA extraction, RNA extraction and
quantization --------------------------------19
4. Synthesis of external cRNA Standard by in
vitro transcription -------------------------20
5. Analysis of SCCA1, A2 Gene Expression by
Real-Time Quantitative RT-PCR ---------------20
6. HPV detection and genotyping ----------------21
7. Cells and cell culture ----------------------22
8. Generation of Cxwj cell----------------------22
9. Detection of SCCA1 and SCCA2 mRNA
expressions by RT-PCR -----------------------23
10. Analysis of SCCA2 promoter activity in
various cell lines --------------------------23
11. Recombinant adenoviral vectors --------------24
12. Determination of adenoviral transduction
efficiency in human uterine cervical cancer
cells-----------------------------------------24
13.In vitro cell viability assay -----------------25
14. Immunoblot analysis --------------------------25
15. Animal studies -------------------------------26
16. Immunohistochemical staining -----------------28
17. Cell death measurement -----------------------29
18. Electron microscopy --------------------------30
19. Visualization and Quantitative analysis of
intracellular autophagic vacuoles ------------30
20. Design of siRNA and transfection -------------31
21. Lysosomal stability assay --------------------32
22. Cytochrome c release and cat L translocation--32
23. Determination of cytosolic cat L activit------33
24. Statistical analysis -------------------------34
Results and Discussions
1. SCC A1 and SCC A2 expression difference in
cervical cancer tissue and associated with
prognosis in patients with cervical cancer----35
2. Using SCC A2 as target gene therapy in cervical
cancer ---------------------------------------39
3. Tumor tissue in cervical cancer show
heterogeneity in vascular pattern and cervical
Squamous cell carcinoma antigens may not
associated with angiogenesis -----------------43
4. SCC A1 function as anti-apoptosis though
inhibition of cathepsin L --------------------45
Summary -------------------------------------------52
Reference -----------------------------------------54
Tables---------------------------------------------68
Figures -------------------------------------------72
簡歷 ----------------------------------------------96
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