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研究生:黎雁行
論文名稱:亞砷酸鈉增加游離輻射所造成人類子宮頸癌細胞之細胞毒性的分子機制探討
論文名稱(外文):Studies of the Enhancement of Sodium Arsenite on Ioning Radiation-Induced Cytotoxicity in Human Cervical Cancer Cells
指導教授:黃海美
學位類別:碩士
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:55
中文關鍵詞:亞砷酸鈉人類子宮頸癌細胞輻射敏感度
外文關鍵詞:sodium arsenitehuman cervical cancer cellradiosensitivitypretreatment
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許多流行病學上的研究指出,亞砷酸鈉為一致癌物質;然而,另一方面其抗癌的性質現在也備受注意。實驗室先前的研究指出,在具有E6基因轉殖的人類類淋巴母細胞(Human Lymphoblastoid cells;TK6)TK6-E6細胞中,亞砷酸鈉可以抑制HPV-16 E6基因的表現,而誘導p53 腫瘤抑制途徑 ( tumor suppressor pathway ),促進細胞凋亡的發生;另外,以 TK6-E6細胞與其parental細胞相比較,TK6-E6細胞株對於亞砷酸鈉處理較敏感,對X-ray照射較具有抗性[Chou and Huang, 2002]。本研究中,所選用的細胞株為具有HPV 感染的人類子宮頸癌 SiHa 細胞。以西方點墨法檢查結果顯示:亞砷酸鈉可以恢復 SiHa 細胞內 p53 蛋白的表現,並且,隨著亞砷酸鈉處理濃度及時間的增加,p53蛋白的表現量亦隨著上升。其下游 p21waf1/cip1 、Mdm2 蛋白的表現也隨著亞砷酸鈉處理時間的增加而上升。另外,由流式細胞分析儀、核酸片段分析實驗(DNA fragmentation assay)以及 Acridine Orange 染色實驗結果顯示:在亞砷酸鈉處理下,SiHa細胞會走向細胞凋亡。然而,X-ray照射不同於亞砷酸鈉處理,並不能恢復細胞內的p53以及其下游 p21waf1/cip1 、Mdm2 蛋白的表現。由SRB survival assay的結果顯示: SiHa細胞在前處理20 μM的亞砷酸鈉4小時後,再以X-ray 照射,相較於無亞砷酸鈉前處理組,可以顯著地增強細胞的輻射敏感度。 相同的處理策略:在5-10 μM的亞砷酸鈉前處理24小時的情況下,亦可顯著地加強SiHa細胞輻射敏感度。此外,SiHa細胞轉殖pCDNA3-p53m質體(含p53(R273H)),在前處理20 μM的亞砷酸鈉4小時後,再給予X-ray照射,並不能抑制前處理亞砷酸鈉所加強的輻射敏感度。因此,SiHa細胞中,前處理亞砷酸鈉所恢復的p53蛋白與所增加的輻射敏感度之間所存在的關係,有待更多後續的實驗加以證實。

Numerous epidemiological studies suggest that sodium arsenite (SA) is a carcinogen. However, recent data have renewed the interest in its anti-carcinogenic properties. More than 90﹪of cervical cancer cells contain oncogenic human papillomaviruses (HPV). These cells usually possess wild-type p53 alleles, but its function is abrogated by HPV E6 oncoprotein through the ubiquitin pathway. Sodium arsenite had been shown to suppress HPV-16 E6 gene, induce p53 tumor suppressor pathway and enhanced apoptosis in E6-transfected lymphoblastoid cells. Additionally, E6-transfected TK6 cells were more sensitive to SA, but more resistant to IR than parental TK6 cells. In the present study, HPV-positive SiHa cervical cancer cells were treated with SA to examine p53 tumor suppressor pathway and apoptotic responses. After treatment with SA, it was found that SA could restore the expression of p53 and its downstream genes, p21 and mdm2, in SiHa cells in dose and time dependent manner. It was also shown that apoptosis occurred in SiHa cells through flow cytometric analysis, DNA fragmentation assay and apoptotic cells staining. In contrast to SA, X-irradiation could not restore p53 tumor suppressor pathway in SiHa cells. Pretreatment with SA could restore p53 function and enhance X-ray-induced cytotoxicity in SiHa cells. However, X-ray-induced cytotoxicity was not reduced by expression of a pCDNA3-p53m(containing mutated p53 at R273H) plasmid. Results from this study suggest that SA may serve as a radiosensitizer for X-ray therapeutic purpose in HPV-positive cancer cells. Therefore, further evidence is required to explore the relationship between SA-restored p53 expression and SA-enhanced radiosensitivity in SiHa cells.

壹、中文摘要……………………………………………………………1
貳、英文摘要……………………………………………………………3
參、緒論…………………………………………………………………5
肆、實驗方法與材料……………………………………………………14
伍、結果…………………………………………………………………20
陸、討論…………………………………………………………………28
柒、參考文獻……………………………………………………………34
捌、圖表…………………………………………………………………45

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Kreppel, H., Bauman, J.W., Liu, J., McKim, J.M., Jr. and Klaassen, C.D. (1993) Induction of metallothionein by arsenicals in mice. Fundam Appl Toxicol 20, 184-9.
Lee, T.C., Tanaka, N., Lamb, P.W., Gilmer, T.M. and Barrett, J.C. (1988) Induction of gene amplification by arsenic. Science 241, 79-81.
Lerman, S. and Clarkson, T.W. (1983) The metabolism of arsenite and arsenate by the rat. Fundam Appl Toxicol 3, 309-14.
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Li, X. and Coffino, P. (1996) High-risk human papillomavirus E6 protein has two distinct binding sites within p53, of which only one determines degradation. J Virol 70, 4509-16.
Lombard, I., Vincent-Salomon, A., Validire, P., Zafrani, B., de la Rochefordiere, A., Clough, K., Favre, M., Pouillart, P. and Sastre-Garau, X. (1998) Human papillomavirus genotype as a major determinant of the course of cervical cancer. J Clin Oncol 16, 2613-9.
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