流體剪應力對膀胱癌細胞週期的影響

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游天賜(Tein-Ssu Yu) 查詢紙本館藏

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機械工程學系

論文名稱

流體剪應力對膀胱癌細胞週期的影響
(The effects of fluid shear stress on the cell cycle of urothelial carcinoma)

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摘要(中)

細胞不受控制的持續分裂是發展成腫瘤的原因，已經有許多研究指出此不受控制的癌細胞中細胞週期素(cyclins)與細胞週期蛋白依賴性激酶(Cyclin-dependent kinases, CDKs)過度表現、細胞週期蛋白依賴性激酶抑制物(cyclin-dependent kinase inhibitors, CKIs)以及腫瘤抑制因子(tumor suppressor)突變或是缺失，導致細胞週期內檢查點機制受到破壞或干擾，使癌細胞無法做出適當回應，獲得抗凋亡的能力，最終發展成腫瘤。治療膀胱癌方法中，最常見就是在手術切除後，在膀胱灌入化學藥物，使藥物在膀胱內停留一段時間，徹底殺死殘留之癌細胞，減少疾病復發機率，藥物停留時間便會增加膀胱內壓力，有研究發現此壓力能抑制癌細胞生長，且與化學藥物配合更能提高細胞凋亡效果，體內有許多機械力存在，流體剪應力也是常見的一種，許多研究發現流體剪應力能使加速細胞生長、走向分化甚至能使細胞凋亡，那流體剪應力對於膀胱癌細胞是否也與壓力有類似效果呢?如果有那又是扮演什麼樣的角色又是透過什麼樣的機制來調控。因此本研究希望透過符合生理條件之流體剪應力刺激膀胱癌細胞，觀察膀胱癌細胞週期的變化。
本研究以剪應力生物反應器刺激膀胱癌細胞BFTC905細胞株，透過流式細胞儀、MTT細胞活性分析以及西方墨點法證實，以流體剪應力12 刺激24小時後，雖然無法誘導細胞週期蛋白依賴性激酶抑制物p18和腫瘤抑制因子p53的表現，但在G1期細胞比例卻增加，此可得知流體剪應力會誘導G1期停滯。再利用MTT分析，也發現在受流體剪應力刺激後，生長被抑制了，最後根據西方墨點法觀察，細胞週期素cyclin D1及細胞週期蛋白依賴性激酶CDK4/6表現量均下降，細胞週期素cyclin E(E1、E2)、cyclin A2和cyclin B1也都下降，但細胞週期蛋白依賴性激酶CDK2與CDC2不受流體剪應力影響，故可知細胞週期停滯在G1前期。然後發現在流體剪應力刺激後，細胞週期蛋白依賴性激酶抑制物p21和p27表現量均上升，p27上升更是明顯，所以cyclin D1-CDK4/6活性下降是透過p21和p27來抑制，並不是透過p18來調控。接著發現在受流體剪應力刺激後，視網膜母細胞瘤蛋白Rb總量下降的非常明顯，可能是細胞慢慢走向凋亡退出細胞週期，因此觀察細胞凋亡與自噬相關蛋白，發現輕鏈3蛋白LC3B與Beclin表現上升，細胞走向自噬(autophagy)，而原態caspase 3(native caspase) 3和原態 caspase 8(native caspase 8)表現量也有上升趨勢，但是截切 caspase 8(cleaved caspase 8)表現量卻沒上升，細胞處於預凋亡(proapoptosis)。故受流體剪應力刺激後透過p53非依賴性路徑調控p21和p27，來抑制cyclin D1-CDK4/6之活性，造成G1期停滯，間接使細胞慢慢退出細胞週期造成細胞自噬與預凋亡。

摘要(英)

Uncontrolled cells continuously grow that is the cause of tumor developments. Substantial researches have pointed that overexpression cyclins and CDKs, mutation or deletion of CKIs and tumors suppressors are common in uncontrolled cells. These situations will destroy or interfere with the checkpoint mechanism of cell cycle. As a result, the cells obtain anti-apoptosis ability and divide inappropriately. Finally it leads to tumorigenesis.
For treatments of bladder cancer, the most common method is the administration of chemicals such as mytomicin C after surgery. The administered chemicals kill the residual cancer cells, reducing the chance of disease recurrence. Increasing the residence time of chemical will increase the pressure within the bladder. Researches in cell biology suggest that pressure can inhibit the growth of cancer cells, and enhance cooperation with chemicals to cell death. There are other mechanical forces in vivo, such as fluid shear stress. Many literatures suggest that fluid shear stress can accelerate cell growth, differentiation or induce apoptosis. Whether fluid shear stress and pressure have a similar effect on bladder cancer cells? If it is true, what kinds of mechanisms regulate the cell cycle? This study aims to simulate bladder cancer cells by fluid shear stress, and investigates its effect on the cell cycle.
This study adopted the shear force bioreactor system to apply the fluid shear stress on BFTC905, a cell line of bladder cancer. The assessments of flow cytometry, MTT assay and Western blot were used to test the cells. For BFTC905 subjected to the fluid shear stress of 12 for 24 hrs, flow cytometry showed that most of the cells stayed in G1 phase, and the cell growth was also inhibited. Tumor suppressor p18 and p53 were not expressed for the cells in Western blot. Our Western blot data showed cyclin D1 and CDK4/6 were down-regulated. Cyclin E (E1, E2), cyclin A2 and cyclin B1 also were down-regulated. But CDK2 and CDC2 were not affected. These results concluded that fluid shear stress induced cell cycle arrest in G1 phase. In addition, p21 and p27 both were up-regulated. Especially p27 was much higher than control. This evidenced that cyclin D-CDK4/6 were regulated by p21 and p27 rather than p18. Moreover it was found that total Rb expression was down-regulated. This suggested that the cancer cells might undergo autophagy and apoptosis. To confirm this, we performed tests on LC3B and Beclin, the autophagy markers, which were shown to be up-regulated. We also found that native caspase 3/8, the apoptosis markers, were up-regulated, but nonetheless cleaved caspase 8 did not show apparent change. This suggested that the cells were not right in apoptosis, but might be in proapoptosis. To conclude our study, fluid shear stress induced G1 arrest by up-regulating p21 and p27 in a p53-independent pathway, which resulted in cyclin D1-CDK4/6 being down-regulated. The bladder cancer cells were then on the way toward autophagy and proapoptosis.

關鍵字(中)

★ 流體剪應力
★ 膀胱癌細胞
★ 細胞週期
★ G1期停滯
★ 自噬
★ 預凋亡

關鍵字(英)

★ fluid shear stress
★ bladder cancer
★ cell cycle
★ G1 arrest
★ autophagy
★ proapoptosis

論文目次

摘要 i
Abstract iii
誌謝 v
目錄 vi
圖目錄 ix
第一章緒論 1
1.1研究動機 1
1.2文獻回顧 6
1.2.1物理刺激對細胞影響 6
1.2.2剪應力生物應器 9
1.2.3細胞週期 11
1.3研究目的 18
第二章實驗方法 25
2.1 細胞來源 26
2.2 細胞培養 26
2.3實驗前置準備 28
2.4剪應力刺激實驗 31
2.5流體剪應力 33
2.5.1馬達轉速設定 33
2.5.2 定常轉速剪應力之計算 35
2.6實驗條件 37
2.7流式細胞儀分析 (Flow cytometric analysis) 37
2.8 細胞活性分析 (MTT assay) 39
2.9蛋白質定量分析 39
2.10蛋白質體電泳 (SDS-PAGE) 41
2.11西方墨點分析法(western blot analysis) 44
第三章結果與討論 48
3.1 實驗前言 48
3.2 細胞週期各階段之分布率 49
3.3生長曲線分析 52
3.4西方墨點分析法之結果與討論 54
3.4.1 流體剪應力對cyclins與CDKs之影響 55
3.4.2 流體剪應力刺激對於CKIs之影響 60
3.4.3 流體剪應力刺激對Rb之影響 63
3.4.4 流體剪應力刺激對凋亡和自噬相關蛋白之影響 65
3.4.5 流體剪應力刺激誘導p53-非依賴性之G1停滯進而造成自噬與預凋亡 69
第四章結論與未來展望 71
參考文獻 73
附錄-實驗耗材、藥品與儀器 86

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指導教授

鍾志昂(Chih-Ang Chung)

審核日期

2016-8-25

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