大腸直腸癌在全世界是第三常見的惡性腫瘤，由於大腸直腸癌病人手術後五年存活率，第三期後就降到60%以下，因此目前有關大腸直腸癌首要的兩個課題，就是早期診斷與更好的化學治療方法。深入地去研究大腸直腸癌分子病理機轉，正是解決這兩大課題的不二法門。胰島素與大腸癌的致癌機轉與發展有關，而5-FU在大腸直腸癌是標準的且重要的化學治療藥物。此外PTTG是一多功能的人類securin，在很多功能上扮演重要角色。我們在蛋白質二維電泳的研究發現，PTTG與大腸直腸癌的侵犯程度有關，而化學治療正是用於侵犯性的大腸直腸癌。另外，PTTG過度的表現在許多腫瘤，而在正常組織它的表現量是低的或沒有的，這種腫瘤專一性表現的特徵，正適合我們臨床上研究針對以PTTG為目標的藥物或標靶治療。所以本研究利用細胞株HT-29，研究5-FU與胰島素對PTTG表現的影響。在實驗中，我們發現在生理值的胰島素會向上控制PTTG。在正常的生理值，胰島素向上控制PTTG呈劑量決定方式，但在大於正常生理值，PTTG向上調控的表現量反而有減少的情形。而在5-FU的實驗，5-FU的確會使PTTG有比較高的表現量，但並不與劑量成正相關，在較高的劑量反而有向上控制表現量減少的情形。在癌症細胞，胰島素控制的路徑與腫瘤的生長、增長和細胞凋亡有關，而這作用可能經由活化致癌的分子目標，如PTTG。我們發現生理濃度的胰島素可以在大腸直腸癌細胞株HT-29向上控制PTTG，意味著一個與胰島素啓動的機轉，與大腸直腸癌發展和（或）進行有關。由於腫瘤轉一性表現，胰島素誘發PTTG，也可能做為大腸直腸癌治療的一個目標。在5-FU與PTTG方面，我們發現5-FU在HT-29約其IC50的濃度時可以誘發PTTG，而且達到作用的高峰。意外的是，在這個濃度之後，誘發的作用有下降的趨勢，這是目前為止所未發現的5-FU對PTTG影響的方式。由於這個發現，我們可以合理解釋為何有些細胞株在DNA受損後被抑制，有些會有較高的表現。重要的是，因為這一個發現，在DNA受損後，PTTG的表現與染色體分離和DNA修補的關聯與機轉，可以得到合理的解釋。而基於這一個發現，我們推測，在DNA受損後，PTTG連結DNA damage response pathways、染色體分離與細胞凋亡，亦即PTTG是細胞在DNA受損後，決定細胞進行DNA修補�細胞周期停止或進行細胞凋亡的關鍵。

Colorectal cancer (CRC) is the 3rd common cancer in the world. Because the five-year survival rate is below 60 % in the patients with CRC, two important respects in CRC researches are early diagnosis and more effective chemotherapeutic drugs. In fact, the studies on molecular pathology of CRC can resolve these two problems. Insulin has a role in the carcinogenesis and developments of CRC, and 5-FU is a standard chemotherapeutic drug for the patients with stage III CRC. As a human securin, PTTG has a major role in many functions. In our studies of 2-D proteomics, PTTG correlates with the invasiveness of CRC. Besides, it is found to be highly expressed in many types of cancer, but the expression of PTTG is, however, low or undetectable in normal tissues. This character of tumor-specific expression is suitable for drug and target therapy. Therefore, we use cell line HT-29 to study the effects of 5-FU and insulin on the expression of PTTG. We have found that insulin in the physiologic level up-regulates PTTG. In normal physiologic level, insulin up-regulates PTTG, in a dose-dependent manner. On the other hand, the induction of PTTG by insulin more than normal physiologic level is decreased. In the studies with 5-FU, PTTG has a higher level after treatment, but not in dose-dependent manner. The up-regulation of PTTG by 5-FU is decreased in a higher dose. In cancer cells, insulin regulated pathways may contribute to the growth, proliferation, and apoptosis of tumors by activating oncogenic molecular targets such as PTTG. We have showed that insulin of bio-physiologic level can up-regulate PTTG in colon cancer HT-29 cell lines. Induction of PTTG by insulin suggests a mechanism by which insulin may contribute to the development and/or progression of colon cancers. To tumor- specific expression of PTTG, induction of PTTG by insulin, consequently, may be a target of colon cancer treatment. In the studies of 5-FU and PTTG, we have found that 5-FU in HT-29 cells can induce PTTG, with a peak effect in a dose around IC50. Interestingly, the induction of PTTG is decreased in a higher dose of 5-FU. This is a new finding in the effect of 5-FU on PTTG. Accordingly, we can realize why PTTG in some studies is suppressed; the others have a higher level. More importantly, the connection of PTTG expression between sister chromatic separation and DNA repair after DNA damage is more reasonable. Based on this finding, we propose that PTTG connects DNA damage response pathways, sister chromatic separation and apoptosis after DNA damage. Therefore, PTTG has a key role after DNA damage, deciding cells to have DNA repair/cell cycle arrest or to progress to apoptosis.

中文摘要……………………………………………………………（I）
英文摘要………………………………………………………… （II）
英文縮寫表……………………………………………………… （IV）

論文內文……………………………………………………………（1）
壹. 緒言……………………………………………………………（1）
一. 大腸直腸癌…………………………………………… （1）
1. 大腸直腸癌流行概況………………………………… （1）
2. 大腸直腸癌的分類…………………………………… （3）
3. 大腸直腸癌在解剖位置上的分佈…………………… （4）
4. 大腸直腸癌致癌機轉（carcinogenesis）………… （5）
5. 大腸直腸癌臨床上的分期與預後…………………… （8）
二. 胰島素（Insulin）與大腸直腸
　　　　 癌……………………………………………………… （9）
1. 胰島素為重要的生長因子…………………………… （9）
2. 胰島素増加類胰島素生長素-1（IGF-1）的生化活性　　　　　　　……………………………………………………… （10）
三. 5-FU……………………………………………………（11）
1. 5-FU的代謝……………………………………………（11）
2. Thymidylate synthase（TS）的抑制………………（12）
3. DNA的錯誤篏入……………………………………… （14）
4. RNA的錯誤篏入……………………………………… （14）
四. PTTG之研究……………………………………………（14）
1. PTTG的promoter………………………………………（15）
2. PTTG蛋白質……………………………………………（15）
3. PTTG的表現……………………………………………（17）
(1) PTTG的表現量是細胞周期依賴性的（cell cycle-
dependent）且是因細胞増長的功能函數………… （17）
(2) PTTG的次細胞部位的表現（subcellular expression）是
細胞周期依賴性的（cell cycle-dependent）……（17）
(3) PTTG的表現具組織專一性與腫瘤專一性………… （17）
(4) PTTG在腫瘤中的過度表現－非突變……………… （18）
4. PTTG的控制……………………………………………（19）
5. PTTG的功能……………………………………………（22）
(1) 致癌基因－細胞轉型與增長…………………………（22）
(2) 細胞周期的進行與有絲分裂…………………………（22）
(3) 轉錄活化（transcriptional activation）的能力（24）
(4) PTTG可與其它的蛋白質結合………………………..（25）
A. PTTG binding factor（PBF）……………………..（25）
B. S10與DnaJ…………………………………………….（25）
C. DNA-PK和Ku-70……………………………………… （25）
D. PTTG與P53之關係…………………………………… （26）
五. 實驗目的………………………………………………（27）

貳. 材料方法…………………………………………………… （28）
一. 大腸直腸癌細胞株HT29之培養與處理………………（28）
1. 材料……………………………………………………（28）
2. 細胞培養………………………………………………（28）
(1) 冷凍細胞解凍程序……………………………………（28）
(2) 細胞繼代培養（Subculture）與細胞計數…………（28）
(3) 細胞冷凍程序…………………………………………（29）
二. 大腸直腸癌細胞株SW480、SW620、HT29之蛋白質萃
取………………………………………………………（29）
三. 蛋白質定量……………………………………………（29）
四. 藥物試驗………………………………………………（30）
1. 化學治療藥物試驗……………………………………（30）
2. 胰島素藥物試驗………………………………………（30）
五. 蛋白質西方漬點電泳法（Western Blotting）……（30）
六. 實驗分析流程…………………………………………（31）
1. 胰島素藥物對PTTG表現影響的實驗分析流程………（31）
2. 抗癌藥物5-FU對PTTG表現影響的實驗分析流程……（32）
參. 結果………………………………………………………… （32）
一. 大腸直腸癌細胞株HT-29的生長曲線……………… （32）
二. 在生理濃度，胰島素向上調控PTTG……………… （33）
三. 5-FU向上調控PTTG……………………………………（34）
肆. 討論………………………………………………………… （34）
一. 胰島素對基因活性的控制－可能包括PTTG…………（34）
二. 在生物生理的濃度胰島素向上控制PTTG蛋白質－在正常生
物生理的濃度，依劑量決定方式……………………（35）
三. 在大於正常生物生理濃度，胰島素向上控制PTTG蛋白質的
效果是減少的…………………………………………（35）
四. 胰島素經由活化PI3K/AKT與Ras-MAPK刺激新的PTTG mRNA
的合成…………………………………………………（37）
五. PTTG的磷酸化…………………………………………（38）
六. 胰島素向上控制PTTG可用來解釋胰島素－大腸癌的轉機
. …………………………………………………………（39）
1. PTTG促進細胞增長的功能：解釋胰島素－大腸癌關聯的機
轉………………………………………………………（39）
2. PTTG的抗細胞凋亡功能：解釋胰島素－大腸癌關聯的機
轉………………………………………………………（41）
七. 在HT-29 p53（-/-）細胞株，加入5-FU後PTTG有較高的表
現量……………………………………………………（41）
八. DNA受損對PTTG的影響……………………………… （42）
1. DNA受損對PTTG的影響－p53的狀態……………… .（42）
2. DNA受損對PTTG的影響－作用時間………………… （43）
3. DNA受損對PTTG的影響－使用劑量………………… （44）
4. DNA受損對PTTG的影響－抑制或先向上控制再抑制 （44）
九. PTTG與DNA修補……………………………………… （46）
1. PTTG與DNA修補－連結DNA damage response path- ways
與染色體分離………………………………………. （46）
2. PTTG與DNA修補－PTTG是被表現的或是被抑制的?..（47）
十. PTTG與細胞凋亡………………………………………（48）
十一. 在DNA受損後，PTTG連結DNA damage response path-
ways、染色體分離與細胞凋亡………………………（49）

伍. 結論………………………………………………………… （50）

參考文獻………………………………………………………… （51）

表一　　臺灣地區(2000年)大腸直腸癌申報發生人數--按年齡分
類……………………………………………………… （2）
表二　　胰島素的生理濃度…………………………………… （68）
表三　　胰島素對PTTG表現的影響…………………………….（69）
表四　　5-FU對PTTG表現的影響……………………………….（70）

圖一　　臺灣地區(2000年)大腸直腸癌申報發生人數--按年齡分
類……………………………………………………… （2）
圖二　　大腸直腸癌的發生途徑……………………………… （4）
圖三　　大腸直腸癌在解剖位置上的分佈…………………… （5）
圖四　　大腸直腸癌致癌機轉：腺瘤－癌症序列…………… （6）
圖五　　與de novo大腸直腸癌有關的扁平狀病灶...……… （7）
圖六　　手術後大腸直腸癌病人的五年存活率……………… （8）
圖七　　5-FU的代謝…………………………………………… （12）
圖八　　5-FU抑制Thymidylate Synthase (TS) 的機轉…… （13）
圖九　　PTTG的關鍵功能區域………………………………… （16）
圖十　　PTTG的promoter含有可被胰島素控制的區域……… （21）
圖十一　PTTG在細胞周期的進行與有絲分裂的角色………….（23）
圖十二　PTTG過度表現造成Aneuploid的機轉…………………（24）
圖十三　PTTG在Western Blotting的位置…………………… （71）
圖十四　大腸直腸癌細胞株HT-29的生長曲線…………………（72）
圖十五　Insulin對PTTG表現的影響……………………………（73）
圖十六　在正常生理值胰島素對PTTG表現的影響，呈劑量決定方
式……………………………………………………… （74）
圖十七　5-FU對PTTG表現的影響……………………………….（75）
圖十八　PTTG連結DNA damage response pathways、染色體分離與
細胞凋亡－決定細胞何時進行DNA修補？何時進行細胞凋
亡？………………………………………………….. （76）

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