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系統識別號 U0007-1105200909404600
論文名稱(中文) 尼古丁及其代謝產物藉由和α7尼古丁受器作用而促進結腸癌細胞轉移之機制探討
論文名稱(英文) Nicotine and its metabolite enhance colon cancer cell migration through reaction with α7-nicotinic acetylcholine receptor – Mechanism study
校院名稱 臺北醫學大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Graduate Institute of Clinical Medicine
學年度 97
學期 2
出版年 98
研究生(中文) 魏柏立
研究生(英文) Po-Li Wei
學號 D102094006
學位類別 博士
語文別 中文
口試日期 2009-05-06
論文頁數 98頁
口試委員 指導教授-林時宜
委員-林仁混
委員-陳維熊
委員-王應然
委員-吳志雄
委員-何元順
委員-張育嘉
中文關鍵字 香煙  尼古丁  尼古丁受器  大腸癌  轉移 
英文關鍵字 Smoking  NNK  Nicotine  colon cancer  migration  metastasis 
學科別分類
中文摘要 抽煙是一個全球性的健康問題,因為它會增加心血管疾病的發生及多種癌症的產生。由於藥物的進步,心血管疾病的治療有明顯地改善,但癌症的治療卻仍有待加強。香煙中含有上百種的致癌物可以破壞細胞中的基因而引發癌症,但更可怕的是菸草中的尼古丁及其衍生物,尼古丁是讓人們對香煙成癮的主要原因而它的多種衍生物例如NNK也是非常強的致癌物。根據流行病學的研究報告顯示長期抽煙會提高大腸直腸癌致死的風險。因為癌細胞轉移是導致病患死亡的主因,而尼古丁及NNK是否會影響結腸癌細胞的轉移目前仍不清楚,因此需要進一步研究。由於尼古丁及NNK可以藉由和α7尼古丁受器結合來發揮其生物功能所以我首先利用定性和定量的PCR來尋找在結腸癌細胞中是否有α7尼古丁受器,再以Trans-well系統及細胞刮傷試驗來研究尼古丁和NNK對結腸癌細胞轉移的影響並觀察和細胞轉移相關的分子改變,最後用抑制劑及小干擾RNA(siRNA)兩種方法來研究接受器在結腸癌細胞轉移的角色。實驗結果發現在HT29及DLD-1兩株結腸癌細胞上都有α7尼古丁受器(α7-nAChR)。然後以致癌物NNK進行第一部份的實驗: 在Trans-well及細胞刮傷試驗中,發現NNK增加了HT29及DLD-1細胞移動的能力。利用抑制劑及小干擾RNA(siRNA)兩種方法了解NNK是藉由α7尼古丁受器的作用而引發了結腸癌細胞中轉錄抑制因子(Snail及ZEB1)的表現增加並進而抑制結腸癌細胞中E-cadherin的轉錄,因此提高了結腸癌細胞的移動能力。接著以尼古丁進行第二部份的實驗: 尼古丁也是藉由α7尼古丁受器的作用而增進結腸癌細胞的移動能力。但異於NNK會改變E-cadherin的表現,尼古丁一方面藉由引發了結腸癌細胞中Fibronectin的轉錄表現增加,另一方面也引發了COX-2的轉錄表現增加,進而讓結腸癌細胞可以利用血管內皮生長因子(VEGF)及其接受器(VEGFR1)產生自我分泌環(autocrine loop)而提高了結腸癌細胞的移動能力。從我們的實驗得知菸草中的致癌物質NNK能透過結腸癌細胞上的α7尼古丁受器而改變E-cadherin轉錄及其轉錄抑制因子(Snail和ZEB1)的表現量來增加結腸癌細胞的轉移能力,而尼古丁則是透過E-cadherin以外的途徑來促進結腸癌細胞轉移。因此讓我們了解要避免抽煙才能遠離大腸直腸癌,而長期抽煙的民眾必須較一般民眾提早開始進行大腸直腸癌篩檢,如果已經罹患大腸直腸癌則應戒菸才能夠讓治療達到最好的效果。
英文摘要 Smoking is a wourdwide health problem. It increased the risk of cardiovascular disease and caused variant cancers. The treatment of cardiovascular disease improved in recent years but the therapy for cancer remains to be improved. There were more than 100 carcinogens within the tobacco and the devastating link between smoking and cancer is nicotine and its metabolites like NNK, which is one of the most potent carcinogens in tobacco. Long-term cigarette smoking increases the risk of colorectal cancer mortality. Because the major cause of cancer death is metastasis, the influence of nicotine and NNK on the migration of colon cancer cells remains to be determined. Since nicotine and NNK exhibited biologic function by receptor binding, receptor for nicotine and NNK in colon cancer cells was identified by PCR and real time PCR. The influence of nicotine and NNK on migration of colon cancer cells was evaluated by trans-well and wound healing assay. The role of receptor for migration was studied by both inhibitor and small interfering RNA (siRNA). The α7 nicotinic acetylcholine receptor (α7-nAChR) was identified in two colon cancer cell lines, HT29 and DLD-1. NNK enhanced HT29 cell migration in both trans-well and wound healing assays. NNK also enhanced DLD-1 cell migration in dose dependent manner. We used inhibitor and siRNA to demonstrate that α7-nAChR mediated NNK-enhanced colon cancer cell migration and down-regulation of E-cadherin were involved in NNK-enhanced migration of colon cancer cells. Furthermore, Snail and ZEB1, two major transcription repressors of E-cadherin in colon cancers, were induced by NNK treatment. Nicotine also enhanced DLD-1 cell migration at concentration of 1 and 10 μM through α7-nAChR. The nicotine-enhanced migration was mediated by induction of another EMT molecule — Fibronectin, but not E-cadherin. Besides, nicotine also increased expression level of COX-2, VEGF and VEGFR1 which might further caused autocrine loop to enhance the colon cancer cell migration. In conclusion, tobacco specific carcinogen, NNK, enhanced colon cancer metastasis through α7-nAChR and E-cadherin — one of the hallmarks of epithelial mesenchymal transition — and its transcription repressors, Snail and ZEB1. Besides, the nicotine also enhanced the colon cancer cell migration through non-E-cadherin pathway. Therefore, smoking should be added into the risk factors of colorectal cancer. For people with long term smoking history, lowering the age may be considered for colorectal cancer screening. The patients with colorectal cancer should get rid of smoking to achieve the optimal therapeutic result.
論文目次 誌 謝 i
縮寫表 ( Abbreviations ) ii
目 錄 ( Contents ) iii
中文摘要 ( Abstract in Chinese ) v
英文摘要 ( Abstract in English ) vii
第一章 緒論 (Introduction) 1
1. 大腸直腸癌的現況 2
2. 香煙與癌症的關係 5
3. 香煙與大腸直腸癌的關係 9
4. 研究動機及重要性 11
5. 研究的假說與特定目的 12
第二章 實驗材料與方法 ( Materials and Methods ) 13
1. 細胞培養(Cell culture)及藥物處理 14
2. 反轉錄-聚合酶連鎖反應 RT-PCR 14
3. 細胞存活率分析(MTT assay) 16
4. 細胞刮傷試驗 (Wound healing assay) 17
5. 細胞移動能力試驗 (Migration assay) 17
6. 小干擾RNA(siRNA)的製備 18
第三章 實驗結果 ( Results ) 19
1. α7尼古丁受器在結腸癌細胞及大腸直腸癌組織中的表現形態 20
2. NNK在結腸癌細胞沒有增生上的效果 20
3. NNK對於結腸癌細胞移動能力的作用 21
4. NNK經由α7尼古丁受器的作用而增强結腸癌細胞移動的能力 22
5. NNK提高了結腸癌細胞中E-cadherin蛋白之轉錄抑制因子(Snail及ZEB1)的表現進而抑制E-cadherin的生成 23
6. 尼古丁經由α7尼古丁受器作用而增强結腸癌細胞移動的能力 25
7. 尼古丁不會影響E-cadherin的轉錄表現 25
8. 尼古丁會增强Fibronectin的轉錄表現 26
9. 尼古丁也會增强COX-2,VEGF和VEGFR1的轉錄表現 26
第四章 討論 ( Discussion ) 28
第五章 結論與展望 (Conclusion and Perspective) 49
第六章 文獻參考 ( References ) 51
第七章 圖表 ( Tables and Figures ) 65
附錄 ( Appendices ) 95
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