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系統識別號 U0026-0812200915270490
論文名稱(中文) 阻斷細胞周圍Fibronectin Matrix與DPP IV間的結合作為具有潛力的抗轉移策略
論文名稱(英文) Blocking the Interaction between Pericellular Fibronectin Matrix and DPP IV as a Potential Anti-metastatic Strategy
校院名稱 成功大學
系所名稱(中) 生物化學暨分子生物學研究所
系所名稱(英) of Biochemistry and Molecular Biology
學年度 97
學期 2
出版年 98
研究生(中文) 李凱君
研究生(英文) Kai-chun Li
電子信箱 s1696412@mail.ncku.edu.tw
學號 s1696412
學位類別 碩士
語文別 中文
論文頁數 113頁
口試委員 口試委員-張明熙
指導教授-鄭宏祺
口試委員-賴明德
口試委員-莊偉哲
口試委員-張敏政
中文關鍵字 第四型雙胜肽水解酶  轉移  纖連蛋白 
英文關鍵字 FN  metastasis  DPP IV 
學科別分類
中文摘要 癌症轉移是癌症病患致死的主要原因,若能有效抑制轉移發生將可延長癌症病患生命。實驗室過去利用大白鼠乳癌model發現,在懸浮狀態下大白鼠乳腺癌細胞MTF7會藉由其表面組裝之纖連蛋白基質(Fibronectin matrix;FN matrix)與肺臟內皮細胞表面之第四型雙胜肽水解酶(Dipeptidyl peptidase IV;DPP IV)結合,促使乳癌轉移至肺臟,因此若可有效抑制此兩分子結合,應可作為有潛力的抗轉移策略。已知癌細胞表面FN matrix來自內源FN及外源FN且其轉移程度與內源FN表達程度呈現密切相關性,故藉由抑制內源FN合成可能使癌細胞表面FN matrix下降,進而避免癌細胞與內皮細胞結合。 的確,利用重組腺病毒載體將FN shRNA送入小鼠乳腺癌細胞4T1抑制其內源FN合成後發現細胞表面FN matrix明顯減少。 動物實驗證明癌細胞周圍FN matrix減少,隨後之肺轉移也顯著地被抑制了。 我們也排除了因抑制FN matrix導致4T1增生及移動能力下降,而使得轉移能力下降的可能性。 此外,為確立FN matrix下降並非由於FN shRNA off-target所致,我們將帶有FN的質體(無法被FN shRNA辨認)送入已被FN shRNA knocked down的4T1中成功回復(rescue)FN matrix的表現,證明FN shRNA序列特異性,確立轉移的抑制現象確實是因抑制內源FN合成所致。 除此之外,找出FN之DPP IV結合位點,並以這些具DPP IV結合能力之FN片段直接阻斷DPP IV與FN的結合也是另一種抗轉移的對策。 經由Far-western及pull down實驗發現FN N端數個重複片段均具有與DPP IV結合的能力,且發現癌細胞表面組裝之FN matrix會暴露這些位點。未來將建立動物實驗觀察這些FN重複片段能否有效藉著結合肺臟內皮細胞之DPP IV而阻斷癌細胞之肺臟轉移。 綜合而論,我們希望藉著了解癌細胞與肺臟內皮細胞之間的結合機制進而達到設計阻斷此結合之藥物來抑制轉移的目的。
英文摘要 Most cancer mortality is attributed to metastatic disease. In rat breast cancer metastasis model, we have demonstrated that the adhesion between fibronectin (FN) matrix assembled on suspended cancer cell (MTF7) surfaces and Dipeptidyl peptidase IV (DPP IV) expressed on lung endothelial cells mediate lung-specific cancer metastasis. Blocking this adhesion is an ideal strategy of preventing metastasis. The FN matrix results from both endogenous (endo-FN) and exogenous sources of dimeric FN. The correlation between the endo-FN expression and the metastatic potential is relatively high. Thus, inhibiting endo-FN synthesis may decrease the FN matrix assembly, consequently preventing cancer cells from arrest in the lung vasculature. Using adenoviral delivery system, we showed that FN shRNA knocked down the endo-FN in metastatic cancer cells thereby inhibiting their pericellular FN matrix. Consistently, the DPP IV adhesion and lung metastasis of these cells were drastically reduced. We confirmed that knocking down the endo-FN expression did not impede cell proliferation and migration. To rule out the off-target effect of FN shRNA on matrix assembly, we performed the rescue assay by transfecting the FN shRNA-expressing cancer cells a shRNA-resistant human FN construct. As expected, we showed the FN matrices on these cells were restored. Alternatively, we determined to identify DPP IV-binding sequence(s) (DBS) from the FN molecule for blocking cancer cells from binding to lung endothelial DPP IV. We found that, in addition to the C-terminal consensus DBS, domains containing type I and II FN repeats in the N-terminal of FN were able to bind to DPP IV with affinities within the range of typical receptor-ligand interactions. We further demonstrated that combining both the C-terminal as well as N-terminal DBS fragments of FN had a synergistic inhibitory effect on DPP IV binding to cancer pericellular FN matrix. Our immediate goal is to test this inhibitory effect in the experimental cancer metastasis assays. Altogether, we have developed two possible anti-metastatic strategies either by preventing FN matrix assembly or by blocking the binding between FN and DPP IV for therapeutic purposes, which may in the near future be applied clinically. III
論文目次 中文摘要--------------------------------------------------I
英文摘要-------------------------------------------------II
誌謝-----------------------------------------------------IV
目錄------------------------------------------------------V
表目錄---------------------------------------------------IX
圖目錄----------------------------------------------------X
附圖目錄------------------------------------------------XII
縮寫---------------------------------------------------XIII
第一章 緒論-----------------------------------------------1
1-1癌症轉移-----------------------------------------------1
1-2臟器特異性癌症轉移-------------------------------------2
1-3 FN/DPP IV與臟器特異性癌症轉移-------------------------3
1-4第四型雙胜肽水解酶
(Dipeptidyl peptidase IV; DPP IV; CD26)-------------------4
1-5纖連蛋白 (Fibronectin; FN)-----------------------------5
1-6核糖核酸干擾 (RNA interference; RNAi)------------------6
1-7 核糖核酸干擾機制--------------------------------------7
1-8核糖核酸之運送-----------------------------------------8
1-9腺病毒 (Adenovirus)------------------------------------9
1-10重組腺病毒載體---------------------------------------10
1-11研究動機---------------------------------------------10
第二章 材料與方法----------------------------------------12
2-1. 實驗材料--------------------------------------------12
2-1-1. 實驗動物------------------------------------------12
2-1-2. 細胞株--------------------------------------------12
2-1-3. 抗體----------------------------------------------12
2-1-4 . 培養液-------------------------------------------12
2-1-5. 緩衝液--------------------------------------------13
2-2. 實驗方法--------------------------------------------18
2-2-1. 繼代細胞------------------------------------------18
2-2-2. 冷凍保存細胞--------------------------------------19
2-2-3. 解凍細胞------------------------------------------19
2-2-4. 抽取細菌質體DNA-----------------------------------20
2-2-5. 電泳法回收DNA-------------------------------------21
2-2-6. 大腸桿菌勝任細胞製作 (competent cell preparation)-22
2-2-7. 限制.切割-----------------------------------------22
2-2-8. 接合作用 (Ligation) ------------------------------23
2-2-9. 菌株轉型作用 (Transform) -------------------------24
2-2-10. CaCl2細胞轉染------------------------------------24
2-2-11. 生產腺病毒---------------------------------------25
2-2-12. 腺病毒感染目標細胞4T1----------------------------26
2-2-13. 腺病毒MOI計算------------------------------------27
2-2-14. RNA萃取------------------------------------------27
2-2-15. 反轉錄聚合.連鎖反應 (RT-PCR) --------------------28
2-2-16. 黏著細胞Condition medium收集---------------------30
2-2-17. TCA濃縮蛋白--------------------------------------30
2-2-18. 黏著細胞蛋白質萃取-------------------------------31
2-2-19. 蛋白質定量---------------------------------------31
2-2-20. SDS-PAGE聚丙醯胺膠體蛋白質電泳法-----------------32
2-2-21. 西方墨點法---------------------------------------33
2-2-22. 黏著細胞表面免疫螢光染色-------------------------34
2-2-23. 懸浮細胞免疫螢光染色-----------------------------35
2-2-24. Microporation細胞轉染----------------------------36
2-2-25. 細胞黏著試驗 (Cell-cell adhesion) ---------------37
2-2-26. 表現MBP重組蛋白----------------------------------37
2-2-27. 純化MBP重組蛋白----------------------------------38
2-2-28. 生物素標記蛋白(Biotinylation) -------------------39
2-2-29. Far western assay (Gel overlay assay) -----------40
2-2-30. 親和性沉澱試驗 (Pull down assay) ----------------41
2-2-31. DP4A binding assay-------------------------------42
2-2-32. DP4A binding assay (FN fragments inhibit) -------43
第三章 實驗結果------------------------------------------44
3-1. 構築可辨認endo-FN序列之shRNA的scramble control------44
3-2. 獲得帶有FN shRNA及scramble shRNA之重組腺病毒--------44
3-3. 以帶有FN shRNA及scramble shRNA之腺病毒感染標的細胞
4T1------------------------------------------------------45
3-4. FN shRNA可抑制4T1細胞endo-FN合成--------------------45
3-5. Endo-FN確實參與癌細胞表面FN matrix組裝--------------46
3-6. 降低癌細胞表面FN matrix組裝可抑制癌細胞與DPP IV黏著-48
3-7. 降低癌細胞表面FN matrix可抑制癌細胞之肺臟轉移-------48
3-8. FN N端30及45kDa片段中數個重複片段存在DPP IV結合位點-50
3-9. DPP IV與Heparin在FN N端結合位點相似性很高且兩者可能
利用相同方式與FN N端重複片段進行結合---------------------50
3-10. 經由計算解離常數 (Kd)得知FN45-4與DPP IV及Heparin
之結合均具特異性且屬於typical ligand-receptor間的結合----51
3-11. FN N端DPP IV結合片段可抑制DP4A與細胞表面FN matrix
結合-----------------------------------------------------52
3-12. 結合FN C端及N端DPP IV結合片段可更加抑制DP4A與細胞表面
FN matrix結合--------------------------------------------52
3-13. 結論-----------------------------------------------53
第四章 討論----------------------------------------------55
4-1. FN在癌症轉移所扮演之角色----------------------------55
4-2. FN shRNA knock down癌細胞endo-FN對抑制細胞表面FN
matrix組裝之效率-----------------------------------------55
4-3. Endo-FN於FN matrix組裝中扮演的角色------------------57
4-4. 使用重組腺病毒載體之優缺點--------------------------57
4-5. FN之DPP IV結合位點----------------------------------59
4-6. 以Far western及pull down assay尋找FN N端重複片段之
DPP IV結合位點-------------------------------------------59
4-7. FN上之肝素 (heparin)與DPP IV的結合位點--------------62
第五章 參考文獻------------------------------------------64
第六章 表------------------------------------------------71
第七章 圖------------------------------------------------75
第八章 附圖---------------------------------------------104
第九章 自述---------------------------------------------113
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