臺灣博碩士論文加值系統

膀胱癌是全球常見的癌症之ㄧ，並且是泌尿道癌症中高死亡率的第二位。它是一種廣泛的組織異質性癌症，發生的部位由膀胱的移形性上皮開始延伸至其他部位。先前我們利用蛋白質體學研究技術找出四株膀胱癌細胞株T24，TSGH8301，RT4與BFTC905具有診斷意義的蛋白質分子標記。在本實驗中我們利用西方墨點法證實這些蛋白質分子標記的表達差異包括HSP27，stathmin，S-與MB-COMT，GST-π，B23與survivin。低程度惡化的RT4細胞株不表達GST-π，且stathmin和survivin的表達也較其它細胞株少；但B23的表達卻比其它細胞株高。HSP27，S-COMT與B23在低程度惡化的細胞株TSGH8301與RT4細胞中的表達是比較高的，可能癌細胞在惡化的過程中，這些蛋白促使細胞明顯增生、抵禦細胞凋亡與增強抗藥性，讓細胞可進行較高程度的惡化。
Thalidomide是一種鎮靜安眠藥，由於在人體內會形成自由基而造成致畸胎的現象，所以在1961年時已經被停用在孕婦。然而在近代的研究中已經證實這個藥物具有抑制血管新生，抑制細胞增生與造成細胞凋亡的活性，所以初步認為它是一種新的抗癌藥物。我們將BFTC905膀胱癌細胞以40-200 μM thalidomide處理，24小時後發現隨著藥物濃度增高細胞的增生有被抑制的現象，但是藥物對細胞並不會有直接的毒性反應。同時經藥物24、48及96小時處理後也沒有明顯的抑制細胞週期的現象。有趣的是，隨著thalidomide濃度的增加細胞中p53蛋白表達明顯的上升但是不會影響細胞表面ICAM-1分子的表達。這個藥物對BFTC905細胞所造成的抑制增生現象，其機轉為何仍有待未來的實驗來證實。

英文摘要
Bladder cancer is one of the common malignancies in the world and represents the second most common cause of death among genitourinary tumors. It includes a wide spectrum of histologically heterogeneous tumor types that arise predominantly from the transitional epithelial (urothelial) lining of the urinary bladder and ureters. Our previous study used proteomic approach to determine the possible protein biomarkers in four bladder cancer cell lines, T24, TSGH8301, RT4 and BFTC905. In this study, we used immunoblotting to reveal and confirm differences in the expression of several markers, including HSP27, stathmin, S- and MB-COMT, GST-π, B23 (nucleophosmin) and survivin. Low-grade RT4 cells did not express GST-π. The expression level of stathmin and survivin was lower but that of B23 was higher in the RT4 than other cell lines examined. Our results indicated that the expression levels of HSP27, S-COMT and B23 proteins were higher in low-grade (TSGH8301 and RT4) than the high-grade cell lines.
Thalidomide, a sedative drug, was withdrawn from the market in 1961 because of free radical-mediated teratogenicity. However, recent studies demonstrated its anti-angiogenic, anti-proliferative and pro-apoptotic properties, and have suggested it to be a novel anti-cancer agent. Treatment with 40-200 μM thalidomide for 24 h concentration-dependently induced the growth inhibition in the BFTC905 bladder cancer cells, but did not exert cytotoxicity or alter cell cycle arrest following 24, 48 and 96 h treatment. Interestingly, thalidomide significantly increased the level of p53 proteins but was without effect on the expression of ICAM-1. The precise mechanisms of thalidomide-induced growth inhibition require further studies.

目錄
中文摘要……………………………………………………………………… 6
英文摘要……………………………………………………………………… 7
壹、背景介紹………………………………………………………………… 8
一、膀胱癌的組織型態………………………………………………… 8
二、膀胱癌的致病分子機制…………………………………………… 8
三、蛋白質體學於膀胱癌研究的應用………………………………… 9
四、Thalidomide的藥理活性…………………………………………12
五、Thalidomide與類似物的抗癌活性…………………………………15
貳、研究目的與實驗設計…………………………………………………… 18
一、研究目的…………………………………………………………… 18
二、實驗設計…………………………………………………………… 18
参、實驗材料與方法………………………………………………………… 20
一、化學藥品及試劑…………………………………………………… 20
二、細胞株……………………………………………………………… 20
三、細胞培養…………………………………………………………… 20
四、西方墨點法………………………………………………………… 21
五、Thalidomide對BFTC905細胞的生長分析……………………… 23
六、Thalidomide對BFTC905細胞的毒性分析………………………23
七、Thalidomide對BFTC905細胞的細胞週期分析………………… 24
八、Thalidomide對BFTC905細胞吸附分子ICAM-1表達的影響……… 25
肆、實驗結果………………………………………………………………… 26
一、不同膀胱癌細胞株中指標蛋白質表達的差異…………………… 26
二、Thalidomide會抑制BFTC905細胞的增生……………………… 27
三、Thalidomide不會直接造成BFTC905細胞的毒性反應………… 27
四、Thalidomide不影響抑制BFTC905細胞的細胞週期停滯………27
五、Thalidomide不影響BFTC905細胞ICAM-1分子的表達………28
伍、討論……………………………………………………………………… 29
一、四株膀胱癌細胞中具有診斷意義的蛋白質分子標記…………… 29
二、Thalidomide對膀胱癌細胞株BFTC905的抗癌活性……………40
陸、結論……………………………………………………………………… 43
柒、參考文獻………………………………………………………………… 44
捌、結果附圖………………………………………………………………… 56

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