臺灣博碩士論文加值系統

卵巢癌是目前最致命的婦科腫瘤。這種癌症在初期因為沒有明顯症狀使得診斷不易，而且在晚期的治療後會有很高的復發風險，同時也容易帶有抗藥性。為了改善目前卵巢癌的治療，我試圖尋找在卵巢癌中可能參與轉移及血管新生過程的重要因子。首先我設計了裸鼠篩選模型，篩選轉移和復發能力較佳的卵巢癌癌細胞。在經過重複三次篩選A2780及SKOV3兩株細胞之後，得到A2780M3及SKOV3M3。在細胞實驗中，我發現我所篩選的A2780M3具有在高細胞密度下持續生長的能力，而SKOV3M3則具有非貼附生長的能力。並且在移行能力及EMT相關蛋白的mRNA表達量也都有變化。同時，我也以A2780M3及SKOV3M3進行了活體實驗，它們不論在皮下或是腹腔形成腫瘤的能力都有顯著增加。而在體內形成腫瘤的切片染色中，我也觀察到A2780M3細胞凋亡的情況較A2780少。由這些實驗我認為我所篩選出來的A2780M3是比較惡性的，因此，我之後使用cDNA微陣列來檢視A2780及A2780M3間的基因變化。在經過篩選之後，我得到三個候選基因：CYP1B1、LOX以及SALL1。在初步的實驗結果中，我使用2,3',4,5'-Tetramethoxystilbene (TMS) 抑制CYP1B1，發現CYP1B1表達量高的細胞，其生長會受到TMS所被抑制。再者，我也建立了Deferoxamine (DFO) 模擬缺氧模型，試圖找出卵巢癌血管新生過程中的重要分子。我個別收集了A2780、SKOV3及OVCAR3三株細胞在有無DFO處理後的條件培養液進行血管新生因子蛋白質晶片分析，並篩選出三個會明顯受到HIF-1調控而增加的血管新生因子：VEGF、IL-6及IL-8。綜合而言，在我的實驗結果中我篩選出可能參與在轉移的候選基因三種，CYP1B1、LOX以及SALL1，以及血管新生的候選基因三種VEGF、IL-6以及IL-8，而這些基因都有可能在卵巢癌中扮演重要的功能。

Ovarian cancer is the most lethal gynecologic malignancy. It not only is hard to be diagnosed at the early stages, but also comes along with a high recurrent rate as well as chemoresistance at the advanced stages even after surgical treatment. In order to improve the current treatment of ovarian cancer, I attempted to identify the important factors potentially involved in the progressions of metastasis and angiogenesis. Firstly, I designed an in vivo selection scheme using nude mice to select ovarian cancer cells tending to metastasis and recurrence. A2780 and SKOV3 were subjected by intraperitoneal injection to selection for three cycles and the corresponding A2780M3 and SKOV3M3 were obtained. In the cell-based experiments, A2780M3 exhibited the ability of proliferation under high cell density, whereas SKOV3M3 evolved the ability of anchorage-independent growth.
The mRNA expression of EMT markers and the ability of migration were also altered in both cell lines. Furthermore, both A2780M3 and SKOV3M3 showed higher tumoral formation ability than their parental cells in boh intraperitoneal and subcutaneous xenografts in nude mice. In addition, immunohistochemical staining indicated that the tumors formed by A2780M3 have less apoptotic signal than those formed by A2780. These results concluded that A2780M3 is more malignant. Therefore, cDNA microarray was further used to differentiate the gene expression profile between A2780 and A2780M3. I then obtained three candidates, CYP1B1, LOX and SALL1, after genomic analysis of the microarray data. In the preliminary experiment, I found that higher CYP1B1 expression is correlated with TMS-mediated suppression of cell proliferation. Secondly, I also established a hypoxia model mimicked by DFO supplement, trying to identify the crucial factors involved in the angiogenesis process of ovarian cancer. I applied angiogenesis array to detect the changes of angiogenic factors in the conditioned media harvested from A2780, SKOV3 and OVCAR3 with or without DFO treatment. Following this, three angiogenic factors upregulated by HIF-1were selected, including VEGF, IL-6 and IL-8. Taken together, the results in my thesis allow me to find three candidate genes involved in ovarian cancer metastasis and three candidate genes involved in ovarian cancer angiogenesis. These candidate genes might play important roles in ovarian cancer progression.

致謝 ·························································································· i
中文摘要 ···················································································· iii
英文摘要 ···················································································· iv
目錄 ·························································································· vi
1、前言 ···················································································· 1
1.1 卵巢癌 ··········································································· 1
1.1.1 卵巢癌的種類 ························································· 1
1.1.2 卵巢癌的起源以及轉移過程 ······································ 2
1.1.3 卵巢癌的治療方式 ··················································· 4
1.1.4 抗藥性 ·································································· 5
1.2 標靶治療 ········································································ 6
1.2.1 以血管內皮生長因子作為目標 ··································· 7
1.2.2 以 Poly ADP-ribose polymerase 為目標 ·························· 8
1.2.3 其他可能目標 ························································· 8
1.3 影響卵巢癌轉移的機制 ····················································· 9
1.3.1 CD44 ···································································· 9
1.3.2 ERRa ··································································· 10
1.3.3 Cathepsin D 及 Cathepsin L ······································· 11
1.3.4 ANGPTL7 ····························································· 12
1.4 研究動機 ········································································ 12
2、材料與方法 ··········································································· 14
2.1 實驗動物 ········································································ 14
2.2 試劑及藥物 ····································································· 14
2.3 實驗材料 ········································································ 16
2.4 抗體 ·············································································· 17
2.5 引子 ·············································································· 17
2.6 儀器 ·············································································· 18
2.7 測量分析軟體 ·································································· 19
2.8 緩衝液、培養液配製 ························································ 20
2.9 細胞培養 ········································································ 24
2.10 鍍 Poly-HEMA 於培養盤 ·················································· 26
2.11 裸鼠篩選模型 ·································································· 26
2.12 細胞增生 ········································································ 27
2.13 細胞非貼附性生長 ··························································· 27
2.14 RNA 萃取 ······································································ 27
2.15 RNA 反轉錄 ··································································· 28
2.16 即時聚合酶連鎖反應 ························································ 28
2.17 細胞移行 ········································································ 28
2.18 活體注射癌細胞······························································· 29
2.19 腫瘤測量 ········································································ 29
2.20 免疫組織化學染色 ··························································· 30
2.20.1 組織固定 ······························································· 30
2.20.2 組織脫水滲蠟 ························································· 30
2.20.3 組織包埋及切片 ······················································ 30
2.20.4 免疫組織化學染色 ··················································· 30
2.21 cDNA 微陣列 ································································· 31
2.22 細胞藥物處理 ·································································· 32
2.22.1 TMS ····································································· 32
2.22.2 DMBA ·································································· 32
2.22.3 DFO ····································································· 32
2.22.4 CS-FBS ································································· 32
2.23 濃縮條件培養液······························································· 33
2.24 蛋白質晶片 ····································································· 33
2.25 酵素連結免疫吸附法 ························································ 33
2.26 西方墨點法 ····································································· 34
2.26.1 蛋白質萃取 ···························································· 34
2.26.2 蛋白質定量 ···························································· 34
2.26.3 鑄膠及蛋白質膠體電泳············································· 34
2.26.4 蛋白質轉印 ···························································· 35
2.26.5 蛋白質免疫染色 ······················································ 35
2.27 線上資料庫 ····································································· 35
2.28 統計分析及製圖······························································· 35
3、結果 ···················································································· 37
3.1 以裸鼠模式模擬卵巢癌細胞轉移暨復發藉以篩選較惡性的
細胞群 ··········································································· 37
3.1.1 評估篩選後的癌細胞在體外培養的細胞增生能力 ··········· 37
3.1.2 評估篩選後的癌細胞在體外移行及的能力 ···················· 38
3.1.3 確認篩選出來的癌細胞在活體內形成腫瘤的能力 ··········· 39
3.1.4 以免疫組織切片化學染色法確認腫瘤生長情況 ·············· 39
3.2 以 cDNA 微陣列的方式偵測篩選前後的癌細胞基因表達量之
變化 ·············································································· 40
3.3 確認CYP1B1 在癌細胞生長中所扮演的角色 ·························· 41
3.4 建立卵巢癌細胞培養的缺氧模型並篩選在缺氧環境下細
胞產生之血管新生因子 ····················································· 41
3.4.1 以蛋白質晶片偵測在缺氧環境下所產生的血管新
生因子 ·································································· 42
3.4.2 以 real-time qPCR 及 ELISA 的方式確認卵巢癌細胞
中所產生之血管新生因子 ········································· 42
3.5 以卵巢癌預後線上資料庫分析蛋白質晶片的結果 ···················· 42
4、討論 ···················································································· 44
4.1 裸鼠篩選模型 ·································································· 44
4.2 經過篩選的卵巢癌細胞之細胞特性 ······································ 45
4.3 在裸鼠中形成腫瘤的能力 ·················································· 46
4.4 cDNA 微陣列 ·································································· 47
4.4.1 Cytochrome P450 1B1 ··············································· 48
4.4.2 Lysyl Oxidase ························································· 51
4.4.3 Sal-like transcription factor 1 ······································· 52
4.5 缺氧模型 ········································································ 53
5、附圖 ···················································································· 55
圖一、以裸鼠模型進行篩選取得的腫瘤 ······································ 55
圖二、比較 A2780 與SKOV3 細胞株在篩選前後增生速度 ·············· 57
圖三、篩選出來的細胞在非貼附性生長的生長情況 ······················· 58
圖四、篩選出來的細胞之型態差異············································· 59
圖五、以 qPCR 測評估細胞在篩選前後出來的 EMT 的相關基因之
相對表達量 ·································································· 60
圖六、以Transwell 方式測量細胞在篩選前後移行能力的變化 ·········· 62
圖七、以皮下注射法評估癌細胞在體內形成腫瘤的速率 ················· 63
圖八、以腹腔注射模擬並評估癌細胞在腹腔中轉移復發的能力 ········ 64
圖九、比較A2780 及A2780M3 生成的腫瘤中細胞增生及細胞凋亡
的訊號差異 ·································································· 66
圖十、以cDNA 微陣列偵測基因表達量並篩選可能基因 ················· 67
圖十一、候選基因在A2780、SKOV3 篩選前後的相對表達量 ·········· 68
圖十二、分析CYP1B1 抑制劑TMS 對於篩選前後的細胞的生長能
力的影響 ····································································· 69
圖十三、以DFO 處理誘導HIF-1a並進行蛋白質晶片偵測變化的血
管新生因子 ·································································· 70
圖十四、VEGF、IL-6 及IL-8 在DFO 處理後的基因表達量 ············· 72
圖十五、SKOV3 在經過DFO 處理後的VEGF、IL-6 及 IL-8 蛋白
質分泌量 ····································································· 73
圖十六、候選基因對卵巢癌患者之無惡化存活期之影響 ················· 74
6、參考文獻 ·············································································· 75

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