臺灣博碩士論文加值系統

神經膠原致癌基因倍增或其蛋白質過度表現的現象，發生於近三成的攝護腺癌症病患身上，且經常伴隨癌細胞轉移及賀爾蒙治療效果降低，使得攝護腺癌症病患的預後較差，增加了治療上的困難，而抑制神經膠原致癌基因的表現，或是其蛋白質所產生的訊息傳遞，則可減弱癌細胞的惡化及抑制癌細胞的增生，更重要的是能夠降低癌細胞的轉移。因此，如何抑制神經膠原致癌基因的表現，為目前癌症治療中的一個重要項目。許多文獻指出，將人類錳型超氧歧化酶基因穩定轉染至多種癌細胞株中，過度表現其蛋白質，皆能導正癌細胞的惡性度、抑制癌細胞的增生及侵犯性，目前研究認為人類錳型超氧歧化酶為腫瘤抑制基因，可作為癌症基因治療的參考。本研究試圖了解神經膠原致癌基因與人類錳型超氧歧化酶在攝護腺癌中所扮演的角色及其相互間的關聯，遂將人類錳型超氧歧化酶基因穩定轉染於神經膠原致癌蛋白表現較高的攝護腺癌細胞株DU145中，觀察人類錳型超氧歧化酶對癌細胞特性的影響。結果發現在攝護腺癌細胞中穩定表現人類錳型超氧歧化酶會造成癌細胞外觀形態改變，並且抑制神經膠原致癌基因及其蛋白質的表現，而明顯降低了癌細胞的生長速率、移動性及轉移能力，為抑制神經膠原致癌基因過度表現的癌症基因治療研究增添了一個新方向，並可進一步了解人類錳型超氧歧化酶抑制癌細胞生長的可能機制。

The HER2/neu gene amplification and/or its protein over-expression is found in approximately 30% of prostate cancer patients and frequently associated with tumor metastasis leading to poor clinical outcome and insensitive to hormone therapy. Repression of HER2/neu gene expression or its signal transduction suppresses the tumor proliferation and metastasis, suggesting the importance of HER2/neu-targeting prostate cancer therapy. Recently, it has been reported that transfection and expression of human manganese superoxide dismutase (huMn-SOD) in many cancer cell lines results in reduced malignancy, decreased tumor proliferation and invasion. Therefore, huMn-SOD is considered to be a tumor suppressor gene for being a candidate agent of cancer gene therapy. This study was designed to understand the roles what HER2/neu and huMn-SOD play and the relationship between HER2/neu and huMn-SOD in prostate cancer cells. The huMn-SOD gene was stably transfected into the prostate cancer cell line DU145 which expressed higher level of HER2/neu. The huMn-SOD-DU145 stable line was found to have reversed morphology, reduced HER2/neu protein expression, decreased growth rate, and low motility and invasion potential. In conclusion, these results provided a new way to the huMn-SOD-mediated HER2/neu-targeting cancer gene therapy and would be beneficial to understanding the repression mechanism of huMn-SOD on HER2/neu-overexpressing cancers.

目錄……………………………………………………………………………………. Ⅰ
表目錄…………………………………………………………………………………. Ⅳ
圖目錄…………………………………………………………………………………. Ⅳ
縮寫表…………………………………………………………………………………. Ⅴ
中文摘要………………………………………………………………………………. Ⅵ
英文摘要………………………………………………………………………………. Ⅶ
第一章、緒論…………………………………………………………………………. 1
第一節、神經膠原致癌基因文獻回顧…………………………………………. 1
壹、 神經膠原致癌基因之背景資料………………………………………. 1
貳、 神經膠原致癌基因和癌症的關係……………………………………. 1
參、 抑制神經膠原致癌基因表現之癌症治療研究………………………. 2
肆、 神經膠原致癌基因與攝護腺癌………………………………………. 3
第二節、錳型超氧歧化酶文獻回顧……………………………………………. 5
壹、 超氧歧化酶之基本資料………………………………………………. 5
貳、 錳型超氧歧化酶………………………………………………………. 5
參、 錳型超氧歧化酶和癌症的關係………………………………………. 6
肆、 錳型超氧歧化酶與攝護腺癌…………………………………………. 7
第三節、實驗緣起與目的………………………………………………………. 8
第二章、材料與方法…………………………………………………………………. 9
第一節、實驗材料及相關儀器…………………………………………………. 9
壹、 細胞株…………………………………………………………………. 9
貳、 細胞培養液……………………………………………………………. 9
參、 質體 DNA ……………………………………………………………. 10
肆、 抗體……………………………………………………………………. 10
伍、 化學藥品試劑…………………………………………………………. 10
陸、 主要儀器及器材………………………………………………………. 12
第二節、實驗方法………………………………………………………………. 13
壹、 西方點墨法……………………………………………………………. 13
貳、 建立Human MnSOD穩定性轉染細胞株…………………………….. 15
參、 超氧歧化酶活性染色法………………………………………………. 16
肆、 細胞生長速率分析……………………………………………………. 17
伍、 細胞移動性分析………………………………………………………. 18
陸、 酵素圖譜活性分析……………………………………………………. 19
第三章、結果…………………………………………………………………………. 20
壹、 以西方點墨法測定p185及人類錳型超氧歧化酶於攝護腺癌細
胞株中的表現…………………………………………………………. 20
貳、 建立穩定性轉染細胞株………………………………………………. 20
參、 以西方點墨法篩選穩定性轉染細胞株………………………….…… 20
肆、 以活性染色法分析穩定性轉染細胞株之人類錳型超氧歧化酶
活性……………………………………………………………………. 21
伍、 穩定表現人類錳型超氧歧化酶穩定細胞株之生長特性……………. 21
陸、 穩定表現人類錳型超氧歧化酶穩定細胞株之細胞移動性分析……. 22
柒、 穩定表現人類錳型超氧歧化酶穩定細胞株之基底膜分解酵素
活性……………………………………………………………………. 22
第四章、討論…………………………………………………………………………. 24
壹、 神經膠原致癌基因與人類錳型超氧歧化酶於攝護腺癌細胞株中
表現的情形……………………………………………………………. 24
貳、 穩定細胞株中人類錳型超氧歧化酶之活性…………………………. 24
參、 人類錳型超氧歧化酶對攝護腺癌細胞株生長的影響………………. 25
肆、 人類錳型超氧歧化酶對攝護腺癌細胞株移動性的影響……………. 26
伍、 未來研究發展…………………………………………………………. 27
第五章、結論…………………………………………………………………………. 28
參考文獻………………………………………………………………………………. 29
表………………………………………………………………………………………. 36
圖………………………………………………………………………………………. 38
附錄……………………………………………………………………………………. 58
表目錄
表一、本論文使用攝護腺癌細胞株之基本資料…………………………………………. 36
表二、人類錳型超氧歧化酶穩定性轉染細胞株之建立…………………………………. 37
圖目錄
圖 1-1. p185HER2/neu 的結構及功能區域圖示……………………………………………..........38
圖 1-2. p185HER2/neu 與上皮細胞生長因子受體家族成員胺基酸序列相似度………………. 39
圖 1-3. 過度表現p185HER2/neu 與癌症預後之關係圖………………………………………... 40
圖 1-4. p185HER-2/neu 於細胞內之訊息傳遞路徑……………………………………………… 41
圖 1-5. 針對 HER2/neu 的治療研究重點………………………………………………… 42
圖 1-6. p185HER2/neu 活化 MAPK 及 PI3K/Akt造成攝護腺癌細胞的增生及存活成
為 androgen independence 之訊息傳遞徑………………………………………… 43
圖 2. -實驗流程圖………………………………………………………………………… 44
圖 3-1. 以西方點墨法分析 p185HER2/neu 及人類錳型超氧歧化酶於攝護癌細胞株
中的表現…………………………………………………………………………… 45
圖 3-2. 以西方點墨法分析 p185HER2/neu 及人類錳型超氧歧化酶於穩定性轉染之
人類攝護腺癌細胞株 DU145 中的表……………………………………………. 47
圖 3-3. 以活性染色法分析攝護腺癌細胞株 DU145 與其穩定性轉染細胞株中
的人類錳型超氧歧化酶之酵素活性……………………………………………… 51
圖 3-4. 攝護腺癌細胞株 DU145 及其穩定性轉染細胞株之細胞外觀型態…………… 52
圖 3-5. 測定分析攝護腺癌細胞株 DU145 與其穩定性轉染細胞株的生長速率…….... 53
圖 3-6. 攝護腺癌細胞株 DU145 與其穩定性轉染細胞株之細胞移動性柱狀分
析圖………………………………………………………………………………... 55
圖 3-7. 攝護腺癌細胞株 DU145 與其穩定性轉染細胞株之細胞移動情形…………… 56
圖 3-8. 攝護腺癌細胞株 DU145 與其穩定性轉染細胞株之基底膜分解酵素活
性分析……………………………………………………………………………... 57

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