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研究生:黃千姿
論文名稱:探討皮膚癌之鱗狀細胞癌與細胞凋亡分子BAK、NOXA、MCL1間的關係
論文名稱(外文):The Study to Evaluate BAK, NOXA and MCL1-mediated Apoptosis in SCC of Skin Cancer
指導教授:王妙媛王妙媛引用關係
指導教授(外文):Nancy M. Wang
學位類別:碩士
校院名稱:國立彰化師範大學
系所名稱:生物技術研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:英文
論文頁數:58
中文關鍵詞:細胞凋亡人類乳頭狀瘤病毒皮膚癌
外文關鍵詞:apoptosisHPVskin cancerBAKMCL1NOXA
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非惡性黑色素瘤是一種常見的皮膚癌。就像其他腫瘤發生的機制一樣,細胞凋亡在腫瘤的發生中扮演重要的角色。在調節細胞凋亡的分子中,BCL2蛋白群扮演重要角色,BCL2家族蛋白依功能可分成促進細胞凋亡蛋白,如NOXA,BAK,BAX,與抑制細胞凋亡蛋白,如BCL2,MCL1等。這兩個subfamily之間的交互作用調控著細胞正常的發展,他們之間平衡失調與腫瘤發展有很大的關係。
本實驗目的在研究皮膚癌與細胞凋亡分子BAK、NOXA、MCL1之間的關係。為了比較腫瘤組織和正常組織中NOXA,MCL1,BAK濃度,用real-time PCR的方法篩檢42對皮膚癌檢體中NOXA,MCL1,BAK的表現量,結果發現,69.6 %鱗狀細胞癌(SCC)的腫瘤組織中,NOXA表現有明顯少於正常組織 (p=0.020),可能SCC腫瘤組織中NOXA濃度較正常組織低時,可能造成NOXA無法和BAK競爭,而阻礙細胞凋亡,導致癌細胞產生。
先前文獻指出引發子宮頸癌的人類乳頭狀瘤病毒(HPV)也可能導致皮膚癌,發現病毒會降解BAK,使細胞無法凋亡。所以此實驗也篩檢HPV,結果篩出HPV6、33、66、16、11、58這幾型,目前還看不出皮膚癌與HPV型態的不同有相關性。意外發現,正常組織也會感染HPV,所以HPV並非是必要因子,可能只是加速因子。
分析皮膚癌BAK的表現時,我們亦偵測到BAK異常轉錄。在29個皮膚癌患者中,有6個病人腫瘤組織的BAK在核苷酸246到320發生缺失,有別於子宮頸癌和卵巢癌,而這些病人缺失這段的DNA卻完好無誤,推測不正常轉錄導致,與先前文獻結果不同,並非為人類乳頭狀瘤病毒(HPV)所致。
Nonmelanoma skin cancer (NMSC) is one of the most frequently diagnosed malignancy in Taiwan. As in many other cancers, deregulation of apoptosis plays an important pathogenic factor in the development of NMSC. Members of BCL2 family regulate and execute many apoptosis pathways. Some of these proteins (such as NOXA, BAK, BAX) are pro-apoptotic, while others (such as BCL2 and MCL1) are anti-apoptotic. A delicate balance of pro-apoptosis and anti-apoptosis is important for a cell, and a shift in this balance of power can push cell toward cancer.
The specific aim of this project is to determine the relationship among NOXA, BAK and MCL1 as the correlation between these genes and clinical pathological features. Forty-two skin cancers including 24 SCC, nine BCC, two malignant melanoma, one mixed type with BCC and SCC and six cases of related skin diseases were examined using quantitative real time PCR. We found a correlation between BAK and MCL1 (p=0.007) but no significant difference between NOXA and MCL1 (p=0.726). There was a significant decrease of BAK in skin cancer (61 %). BAK expression was found too low and it may affect BAK oligomerization activity in mitochondria cause a shift to anti-apoptotic activity. Therefore, BAK is the key regulator in skin cancer via apoptosis pathway. In addition, there were HPV6, 11, 16, 33, 58 and 66 detected in this study, but no significant correlations were found between skin cancer types and HPV types.
Furthermore, analysis of BAK expression using nested RT-PCR and DNA sequencing revealed a major abnormal transcript in 20.7 % skin cancer which was not found in neither cervical cancer nor ovary cancer tissues. This 250 bp fragment lacking exon 2 and exon 3 were to result from possible aberrant splicing rather than somatic deletion. Deletion of BAK in human skin cancer is independent of HPV infection.
Abstract (English) ………..………………………………..Ⅰ
Abstract (Chinese) ……. …………………………………..Ⅱ
1. Introduction………………………………………………1
2. Materials and methods…………………………………..9
3. Results…………………………………………………...14
4. Discussions……………………………………………... 18
5. References……………………………………………….21
6. Figures…………………………………………………...24
7. Tables………………………………………………….....43
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