研究探討層流剪應力對泌尿上皮細胞癌於細胞週期運作之影響與機轉

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賴家緯(Chia-Wei Lai) 查詢紙本館藏

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生醫科學與工程學系

論文名稱

研究探討層流剪應力對泌尿上皮細胞癌於細胞週期運作之影響與機轉
(Investigation of the Effect of Laminar Shear Stress on Mitotic Cell Cycle of Human Urothelial Carcinoma)

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摘要(中)

惡性腫瘤的產生由細胞不正常分裂累積所導致，過去對於各種癌症研究中皆可發現其細胞內部中的細胞週期素、細胞週期依賴性激酶表現異常，或是細胞週期素依賴性激酶抑制物及腫瘤抑制因子的缺失。種種證據皆指向細胞週期的異常在於細胞失去調控上述相關蛋白質的功能，使細胞能不斷生長、複製、分裂進而導致惡性腫瘤的產生。在泌尿系統中，各器官之內層主要由泌尿上皮(或稱移行上皮)所構成，因此在病理機制上各器官極為相似。泌尿上皮癌細胞在體內會受到層流剪應力的刺激，此應力來自組織間隙流、血管血液流等，且強度大小不一，於本實驗使用之層流剪應力強度範圍為2~12dyne/cm2，而比其他器官特殊在於輸尿管中尿液的流動，其強度約為3~5dynes/cm2。本研究藉由平行板式流動系統產生層流剪應力來刺激泌尿上皮癌細胞，並透過西方點墨法、影像式細胞分析儀及細胞生長率實驗得知，在相對弱之層流剪應力(2、4 dyne/cm2)下，細胞對於外界變化無太大反應；而相對強之層流剪應力(8、12 dyne/cm2)沖刷下，在刺激第8小時開始，原本停留在G1期的細胞減少，同時進入S期的細胞增加，當刺激時間拉長到12小時，轉向進入G2/M期累積。為了瞭解G2/M顯著上升的原因，我們以四種層流剪應力強度分別刺激12小時去分析各時期相關蛋白質的表現，並發現調控G1期的Cyclin D/CDK4/CDK6、G1/S期的Cyclin E/CDK2、S/G2的Cyclin A/CDK2及G2前期的Cyclin A/CDK1隨強度上升表現量降低，而調控G2晚期和M期的Cyclin B卻隨著強度上升表現量顯著提高，而調控CDK1磷酸化的wee1、CDK1於Tyr15磷酸化、p21的表現量都與Cyclin B趨勢相似，證明Cyclin B與CDK1的結合受到阻擋，而使細胞無法順利由G2晚期推向M期導致細胞停滯在G2/M期。另外，從細胞生長率實驗中同樣發現相似的結果，在刺激12小時細胞數隨著強度上升而減少，並且在連續培養6天內細胞數都顯著低於靜態控制組。為了進一步探討細胞內訊息傳遞的路徑，我們根據文獻鎖定p21上游的SMAD家族並藉由西方點墨法分析，在刺激12小時後smad1/5磷酸化表現量隨著強度上升顯著增加而smad2/3磷酸化則無明顯變化，說明以smad1/5做為傳遞路徑的BMP受器被開啟。最後，為了進一步做驗證，我們加入BMP路徑的抑制劑dorsomorphin後再以相同條件刺激，結果發現smad1/5磷酸化及其下游p21包含細胞週期相關蛋白質表現量之趨勢皆有平緩的現象，說明層流剪應力的效果可能被阻隔。由以上證據說明層流剪應力很可能間接或直接活化BMP受器，開啟smad路徑使p21表現進而去影響細胞週期停滯。

摘要(英)

Mechanical microenvironment plays important roles in cell development, maintenance, and in cellular responses and functions. Laminar shear stress is one of important mechanical force in human body especially at tumor. Because according to tumor size, LSS intensity is also different. In urinary system, LSS is generated by blood flow, Interstitial fluid flow or lymph flow to stimulated urothelial. In this study, human bladder cancer cells; BFTC-905 cells were treated with 2, 4, 8, and 12 dynes/cm2 LSS separately where each one was sheared for 1, 4, 8, and 12 h, respectively, and then subjected to cell cycle analysis by using both cellular and molecular assays. The image cytometric result shows that LSS with intensity of ≥ 8 dynes/cm2 enabled to induce G2/M arrest that the percentages of cells in G2/M significantly increased 2.2 folds and 2.4 folds after sheared with 8 and12 dynes/cm2, respectively, for 12 h. The growth rate of cells treated with 12 dynes/cm2 for 12 h remarkably reduced 0.8 fold as compared to the group without LSS in day 6. In addition, we found that the protein expression levels of Cyclin B1, p-CDK1(Y15), wee1 and p21 up regulated while CDK1, CDK2, CDK4, CDK6, Cyclin A2, Cyclin D1, Cyclin E1 down regulated along with increase of LSS intensity, demonstrating that the LSS-induced cell cycle arrest was occurred at G2/M phase. Moreover, we investigated Smad family to clear related pathway between LSS and BFTC-905, and we found the protein expression levels of p-smad1/5 and smad4 up regulated while smad1, smad2/3, p-smad3 no significant change. It means BFTC-905 will transmit LSS signal by BMP pathway. These results showed that the LSS may turn on BMP signal pathway and inhibit the proliferation of urothelial carcinoma growing in urinary system.

關鍵字(中)

★ 層流剪應力
★ 細胞週期停滯
★ 泌尿上皮癌細胞
★ BMP訊息傳遞路徑
★ 機械微環境

關鍵字(英)

★ Laminar Shear Stress
★ urothelial carcinoma
★ cell cycle arrest
★ BMP signal pathway
★ mechanical microenvironment

論文目次

致謝 IV
摘要 V
Abstract VII
目錄 IX
表目錄 XII
圖目錄 XIII
第一章緒論 1
1.1 前言 1
1.2 研究目的 3
第二章文獻回顧 4
2.1 泌尿系統與癌症 4
2.1.1 發生率統計 4
2.1.2 泌尿道上皮癌致病因素 6
2.2 細胞週期 6
2.2.1 循環過程 7
2.2.2 調控機制 10
2.3 機械力刺激對細胞之影響 17
2.3.1 層流剪應力 18
2.3.1 血管內之層流剪應力 18
2.3.2 組織間隙流之層流剪應力 19
2.3.3 輸尿管內之層流剪應力 21
第三章材料與實驗方法 22
3.1 實驗藥品與儀器 22
3.1.1 細胞培養 22
3.1.2 西方點墨法試劑 23
3.1.3 儀器設備 25
3.2 平行板式流動系統(Parallel-plate flow system) 27
3.3 實驗方法 31
3.3.1 細胞繼代、保存與解凍 31
3.3.2 實驗之玻片準備 33
3.3.3 Two-step cell cycle分析 33
3.3.4 蛋白質定量分析 34
3.3.5 膠體電泳(SDS-PAGE) 36
3.3.6 西方點墨法(Western Blot) 38
3.4 實驗設計 42
第四章結果與討論 45
4.1 層流剪應力對細胞週期分佈之影響 45
4.1.1 層流剪應力強度變化與細胞週期 45
4.1.2 沖刷時間變化與細胞週期 47
4.2 層流剪應力對相關週期蛋白質表現之影響 50
4.2.1 調控細胞週期-G1期之蛋白質表現變化 50
4.2.2 調控細胞週期-G1/S轉換之蛋白質表現變化 51
4.2.3 調控細胞週期-S/G2轉換之蛋白質表現變化 52
4.2.4 調控細胞週期-G2與G2/M轉換之蛋白質表現變化 53
4.2.5 調控細胞週期-p21與Wee1蛋白質表現變化 55
4.3 層流剪應力對泌尿上皮癌細胞生長之影響 57
4.4 層流剪應力對泌尿上皮癌細胞週期影響之機轉 61
4.4.1 層流剪應力刺激對SMAD家族之影響 61
4.4.2 層流剪應力刺激下抑制劑對細胞週期之影響 63
第五章結論 69
第六章未來展望 72
參考文獻 74
附錄 84

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指導教授

李宇翔(Yu-Hsiang Lee)

審核日期

2017-8-4

推文