癌細胞的轉移是目前引發癌症病患死亡的主要原因，目前的治療方式主要是手術、化學療法或者是放射線治療為主，但是儘管已經有治療癌症的方法不過轉移目前還是難以被治療。1920 年代 Otto Warburg 發現癌細胞代謝反應與正常細胞截然不同，其中的特徵為葡萄糖的使用量增加並產生乳酸進而促進癌細胞的生長，然而代謝的改變是否會影響癌細胞的轉移還不是特別清楚。因此在果蠅卵巢裡有一群細胞稱為邊境細胞，這群細胞會集體遷移並穿越護士細胞最後在 stage 10 抵達卵母細胞所以可以模擬癌細胞的轉移與侵襲。我們發現在邊境細胞不表現延胡索酸水合酶的情況下會影響邊境細胞和濾泡細胞 (Follicle cell) 遷移。然而延胡索酸水合酶催化活性的改變並不影響邊境細胞遷移，除此之外我們也進一步去影響代謝反應並觀察邊境細胞遷移的情形，結果也發現不影響邊境細胞遷移。根據這些結果表明延胡索酸水合酶影響邊境細胞遷移與催化活性和代謝反應的改變無關。

The metastasis of cancer cells is currently the main cause of death of cancer patients. The current treatment methods are mainly surgery, chemotherapy or radiation therapy. However, although there are methods for treating cancer, metastasis is still difficult to be treated. In the 1920s, Otto Warburg discovered that the metabolic response of cancer cells is completely different from that of normal cells, which is characterized by increased use of glucose and production of lactic acid to promote the growth of cancer cells. However, it is not particularly clear whether changes in metabolism affect the metastasis of cancer cells. Therefore, there is a group of cells in the ovary of Drosophila called border cells. This group of cells will collectively migrate and pass through nurse cells and finally reach the oocyte at stage 10, so it can simulate the metastasis and invasion of cancer cells. We found that border cell and Follicle cell migration will be affected when border cells do not express fumarate hydratase. However, changes in the catalytic activity of fumarate hydratase did not affect border cell migration. In addition, we also further affected the metabolic reaction and observed border cell migration, and found that it did not affect border cell migration. According to these results, it is shown that the influence of fumarate hydratase on border cell migration has nothing to do with changes in catalytic activity and metabolic reactions.

論文審定書....................................................................................................................... i
誌謝.................................................................................................................................. ii
中文摘要......................................................................................................................... iii
Abstract............................................................................................................................ iv
第一章 緒論.................................................................................................................... 1
1.1 癌症................................................................................................................... 1
1.2 癌症代謝........................................................................................................... 2
1.3 檸檬酸循環....................................................................................................... 3
1.4 延胡索酸水合酶 (fumarate hydratase)............................................................ 5
1.5 邊境細胞遷移模式........................................................................................... 8
第二章 實驗材料與方法.............................................................................................. 10
2.1 Drosophila stocks............................................................................................. 10
2.2 Drosophila ovary dissection and Immunohistochemistry .................................11
2.3 Mosaic clone analysis....................................................................................... 15
第三章 實驗結果.......................................................................................................... 17
3.1 Fumarase 1 表現在邊境細胞.......................................................................... 17
3.2 敲低 Fumarsae 1 不影響邊境細胞遷移....................................................... 17
3.3 缺乏 Fumarase 1 影響邊境細胞遷移........................................................... 18
3.4 邊境細胞遷移不受 Fumarase 1 的催化活性影響........................................ 19
3.5 缺乏 Fumarase 1 影響拉伸濾泡細胞 (Stretched follicle cell) 遷移.......... 19
3.6 延胡索酸的累積不影響邊境細胞遷移......................................................... 19
第四章 討論.................................................................................................................. 21
實驗結果圖.................................................................................................................... 23
Figure 1. 果蠅 Fumarase 1 與人的 Fumarase 胺基酸序列比對...................... 24
Figure 2. Fumarase 1 在邊境細胞中表達以及本研究使用的突變基因座........ 25
Figure 3. GAL4-UAS system 以及敲低 fumarase 1 位置示意圖..................... 26
Figure 4. 利用遺傳雜交方式獲得表現一個 copy 的 fumarase 1G0290 突變及
UAS-fumarase 1 RNAi34797 實驗設計圖................................................................... 27
Figure 5. 表現一個 copy 的 fumarase 1G0290 突變及 UAS-fumarase 1 RNAi34797
對於邊境細胞群體遷移影響不大........................................................................ 28
Figure 6. 利用遺傳雜交方式獲得表現一個 copy 的 fumarase 1G0290 突變及
UAS-fumarase 1 RNAi51779 實驗設計圖................................................................... 29
Figure 7. 表現一個 copy 的 fumarase 1G0290 突變及 UAS-fumarase 1 RNAi 51779
對於邊境細胞遷移影響不大................................................................................ 30
Figure 8. 利用遺傳雜交方式獲得表現一個 copy 的 fumarase 1G0290 突變及
UAS-fumarase 1 RNAi76516 實驗設計圖................................................................... 31
Figure 9. 表現一個 copy 的 fumarase 1G0290 突變及 UAS-fumarase 1 RNAi76516
對於邊境細胞遷移影響不大................................................................................ 32
Figure 10. 利用遺傳雜交方式獲得表現一個 copy 的 fumarase 1G0290 突變及
UAS-fumarase 1 RNAi 51779 和 UAS-fumarase 1 RNAi 34797 實驗設計圖.................. 33
Figure 11. 表現一個 copy 的 fumarase 1G0290 突變及表現兩個 UAS-fumarase
1
RNAi 51779 和 UAS-fumarase 1 RNAi 34797 對於邊境細胞遷移影響不大 ............... 34
Figure 12. 邊境細胞遷移需要 Fumarase 1 並且不受催化活性的影響........... 36
Figure 13. 濾泡細胞遷移需要 Fumarase 1 ......................................................... 37
Figure 14. 降低邊境細胞內的延胡索酸不影響其遷移能力.............................. 39
Figure 15. 缺乏 Fumarase 1 的單顆邊境細胞較鄰近的正常對照組細胞遷移能
力較差.................................................................................................................... 41
參考資料........................................................................................................................ 42
附錄................................................................................................................................ 56
附錄一. Drosophila oogenesis 和邊境細胞遷移示意圖 ..................................... 56
附錄二. Mosaic clone 示意圖............................................................................... 57

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