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研究生:洪佑霖
研究生(外文):Yu-Lin Hung
論文名稱:探討Protocadherin 10對大腸直腸癌細胞之細胞凋亡和幹細胞特性之影響
論文名稱(外文):The effects of Protocadherin 10 on apoptosis and stemness in colorectal cancer
指導教授:楊雅倩
指導教授(外文):Ya-Chien Yang
口試委員:林亮音蘇剛毅潘思華蔡明宏
口試委員(外文):Liang-In LinKang-Yi SuSzu-Hua Pan
口試日期:2015-06-25
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:醫學檢驗暨生物技術學研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:中文
論文頁數:67
中文關鍵詞:大腸直腸癌PCDH10細胞凋亡癌幹化能力
外文關鍵詞:Colorectal cancerPCDH10ApoptosisCancer stemness
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大腸直腸癌於美國及台灣之癌症致死原因皆排名第三名,其致死原因主要是由於遠端器官轉移,其容易轉移之器官包括肝臟及肺臟。雖然至今陸續發展多種抗癌療法或改進之合併性治療,但預後差之事實依然存在,故鑑定出此癌症之分子機轉仍有助於其診斷與治療。實驗室近幾年之研究透過細胞增生、非貼附性生長、遷移、侵襲等體外試驗,以及動物試驗利用異種移植模型進行腫瘤生成及肝臟轉移分析,其結果皆顯示PCDH10於大腸直腸癌扮演抑癌基因之角色。本論文主要分為三部分探討,首先證實PCDH10能增加大腸癌細胞自發性細胞凋亡外,於高氧化壓力環境下亦可明顯促進細胞凋亡;第二部分則以癌幹細胞特性為主題,結果發現PCDH10可減少癌細胞球狀體形成之比例,且能抑制其癌幹細胞標記CD133、Bmi-1、Nanog及Sox2之表現;第三部份則進一步探討PCDH10傳遞路徑調控細胞凋亡及癌細胞幹化能力之分子機轉,結果顯示:PCDH10透過抑制PI3K/AKT及Sonic Hedgehog訊息傳遞路徑之活化達到促進細胞凋亡及抑制癌幹細胞之潛能。綜合以上結果,我們更加確認PCDH10於大腸直腸癌扮演重要的抑癌角色並揭露其調控機制。

Colorectal cancer (CRC) is the third leading cause of cancer death in the United states and Taiwan. Most deaths of CRC are associated with distant metastasis, including liver and lung. Although recent researches have acclaimed that many alternative treatments to attenuate tumor progression, but not always get good prognosis. Therefore, an improved understanding of the molecular mechanism involved in CRC may provide new insights into CRC diagnosis and treatment. In previous studies , we demonstrated that PCDH10 is a crucial tumor suppressor gene in CRC by cell proliferation, anchorage-independent growth, migration and invasion assay in vitro. Moreover, we also performed tumorigenesis and liver metastasis experiments with in vivo xenograft tumor models. The results confirmed that PCDH10 is a CRC-associated tumor suppressor gene. In the study, there are three specific aims. The first was focused on the role of PCDH10 in regulation of apoptosis. The results indicated that PCDH10 increased not only spontaneous apoptosis, but also oxidative stress-induced apoptosis. The second part was focused on the effect of PCDH10 on cancer stemness. The results showed that re-expression of PCDH10 decreased spheroid formation and down-regulated cancer stem cell markers, including CD133, Bmi-1, Nanog and Sox2 in CRC cells. In the third part, we investigated the pathways involved in PCDH10-modulated apoptosis and stemness potential. The results revealed that PCDH10 might down-regulate PI3K/AKT and Sonic Hedgehog signaling pathways to induce apoptosis and inhibit stemness potential. Taken together, we further confirm that PCDH10 plays a crucial role in tumor suppression and disclose the molecular mechanisms regulated by PCDH10.

誌謝 i
摘要 ii
英文摘要 iii
縮寫表 iv
一、緒論 1
1. 大腸直腸癌簡介 1
2. 大腸直腸癌分期 2
2.1. Dukes分期系統 2
2.2. TNM分期系統 3
2.3. AJCC/UICC分期系統 4
3. Cadherin家族簡介 5
4. Protocadherin 10 (PCDH10)之發現及癌症相關研究 6
5. 細胞凋亡與腫瘤 7
6. 癌幹細胞簡介 8
7. 細胞訊息傳遞路徑 10
7.1. 細胞訊息傳遞與癌症 10
7.2. PI3K/AKT訊息傳遞路徑與癌細胞 10
7.3. Sonic hedgehog (SHH)傳訊路徑與癌細胞 10
二、研究目標 12
三、實驗材料與方法 13
1. 試劑等相關材料及抗體 13
2. 大腸直腸癌細胞株 13
3. 流式細胞檢測細胞凋亡 14
4. 癌細胞球狀體培養 14
5. 細胞轉染 15
6. 蛋白質萃取與定量 15
7. 西方墨點法 16
8. RNA萃取 16
9. 反轉錄合成互補DNA 17
10. 即時定量聚合酶連鎖反應 18
11. 統計分析 18
四、實驗結果 19
1. PCDH10可增加大腸癌細胞自發性細胞凋亡 19
2. PCDH10可增加氧化壓力引起之細胞凋亡以及程度差異性 19
3. PCDH10可抑制癌細胞球狀體生成 20
4. PCDH10大腸直腸癌細胞株之幹細胞相關分子表現情形 20
5. PCDH10可降低PI3K/AKT訊息傳遞 22
6. PCDH10對Hedgehog訊息傳遞之影響 22
五、討論 23
六、圖 27
七、表 46
八、附圖 47
九、參考文獻 53


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