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系統識別號 U0026-1607201414471400
論文名稱(中文) 探討新穎微管抑制劑 MPT0B098 作用於缺氧下所引發的上皮細胞轉殖成間質細胞之成效
論文名稱(英文) Study the Effect of Novel Microtubule Inhibitor MPT0B098 on Epithelial to Mesenchymal Transition under Hypoxia Condition
校院名稱 成功大學
系所名稱(中) 分子醫學研究所
系所名稱(英) Institute of Molecular Medicine
學年度 102
學期 2
出版年 103
研究生(中文) 蔡伊庭
研究生(英文) I-Ting Tsai
學號 T16014030
學位類別 碩士
語文別 英文
論文頁數 47頁
口試委員 指導教授-張俊彥
口試委員-張玲
口試委員-郭靜娟
中文關鍵字 缺氧  轉移  上皮間質轉化  微管抑制劑 MPT0B098  轉化生長因子-β 
英文關鍵字 hypoxia  metastasis  Epithelial to mesenchymal transition (EMT)  microtubule inhibitor MPT0B098  TGF-β 
學科別分類
中文摘要 上皮間質轉換(EMT)起先是在胎胚發育時期被發現。而近年來得知其與腫瘤細胞從良性轉化成惡性腫瘤有關。此外,越來越多的證據顯示經由缺氧誘導因子(HIF)可以調節一些引發上皮細胞轉殖成間質細胞的訊息路徑。我們實驗室先前找到一個新穎的微管抑制劑—7-芳基-二氫吲哚-1-苯磺胺酰胺(MPT0B098),其不同於其他微管抑制劑,它藉由調節人類抗原 R (HuR)來抑制缺氧誘導因子-1α 的核醣核酸以及蛋白質的表現 。本研究米進一步探討 MPT0B098 對EMT的進行及機轉之影響。由於細胞型態的變化是EMT 發生的過程很重要標誌,我們首先觀察到缺氧環境下細胞的型態有明顯的變化,同時 MPT0B098 可以有效抑制細胞從上皮細胞轉化成間質細胞型態。從這裡我們得知 MPT0B098 對於調控 EMT 來說是很有潛力的。接下來我們也發現 MPT0B098 確實能夠抑制 EMT 相關的蛋白。另外,MPT0B098 相較於其他微管抑制劑有著更加顯著抑制效果。在缺氧的環境下,我們觀察到 OECM-1 細胞有高度的侵略性以及移動力,而在 MPT0B098 的影響下可以降低細胞的移動能力。接著探討 MPT0B098 的機制,我們發現轉化生長因子-β活化的 Smads 訊息傳遞訊號能有效的被 MPT0B098 隨著濃度變化給抑制。並且在深入研究後我們發現 MPT0B098 是透過抑制細胞因子轉化生長因子-β 訊息核糖核酸以及蛋白質的表現量。由於在缺氧環境下缺氧誘導因子-1α能夠和細胞因子轉化生長因子-β驅動子結合,並且調控他們的轉錄能力,於是我們擬進一步探討 MPT0B098是否是透過缺氧誘導因子-1α來調控細胞因子轉化生長因子-β。結果顯示直接降低缺氧誘導因子-1α轉譯表現量對細胞因子轉化生長因子-β 沒有影響。接著我們又進一步探討 MPT0B098 在常氧下對細胞因子轉化生長因子-β的影響,結果顯示在常氧環境下 MPT0B098 的抑制效果仍然存在。綜此,本研究首次闡明一個新穎的微管抑制劑藉由調控細胞因子轉化生長因子-β訊息傳遞路徑來抑制缺氧下所引發的上皮間質轉化。
英文摘要 Epithelial to mesenchymal transition (EMT) is first recognized as a characteristic of embryogenesis in development. Recently, it has been involved in tumor transformation from benign to malignant tumor and cancer metastasis. Moreover, evidence has demonstrated that regulation of EMT signaling pathways is associated with HIF-1α, under hypoxia condition. We recently discovered a novel microtubule inhibitor, 7-aryl-indoline-1-benzene-sulfonamide (MPT0B098). Distinguished from other microtubule inhibitors, MPT0B098 destabilizes the HIF-1α mRNA under hypoxia by inhibiting human antigen R (HuR) translocation from the nucleaus to cytoplasm. Therefore, the objections of this study were to identify the idea and possible underlying mechanism of MPT0B098 on EMT inhibition under hypoxia. We firstly observed that MPT0B098 could inhibit a change of OEC-M1 cells from epithelial to mesenchymal morphologies under hypoxia, indicating that MPT0B098 potentially modulated the process of EMT. Furthermore, our data showed that the protein levels of mesenchymal markers, including N-cadherin, twist, slug and vimentin, were down-regulated in a concentration-dependent manner in OEC-M1 cells treated with various concentrations of MPT0B098 under hypoxia. In addition, MPT0B098 exerted a stronger inhibitory activity against EMT-related proteins than other microtubule inhibitors. Furthermore, we observed that the migratory ability of OEC-M1cells decreased in a concentration-dependent manner when the cells are treated with various concentrations of MPT0B098 under hypoxia. To investigate the mechanism of MPT0B098 action against EMT, we found that TGF-β-induced phosphorylation of receptor-associated Smads were effectively blocked through decreasing TGF-β mRNA and protein expression when cells treating with MPT0B098 in a concentration-dependent manner under hypoxia. Since the interplay between HIF-1α and TGF-βis well-known, we then knocked down HIF-1α expression under hypoxia. Surprisingly, the inhibitory activity of HIF-1α-targeted siRNA on canonical TGF-β signaling cascade is no difference between cells treated with or without MPT0B098 treatment. Moreover, we also demonstrated that MPT0B098 could inhibit TGF-βs protein expressions in a concentration-dependent manner under a normoxia condition. Taken together, results from this study may provide a novel insight into mechanism of action of microtubule inhibitor for inhibiting EMT.
論文目次 Chinese Abstract II
English Abstract IV
Acknowledgments VI
Table X
Figures XI
Abbreviations XII
Introduction 1
1. Metastasis 1
1-1 Hypoxia 2
1-2 Epithelial-to-Mesenchymal Transition (EMT) 3
1-3 Transforming growth factor‑β (TGF-β) signaling 3
1-4 TGF‑β signaling in EMT 4
1-5 Transcriptional regulation of EMT by Smads in TGF-β signaling 5
1-5-1 Snail family transcription factors 5
1-5-2 ZEB family transcription factors 6
1-5-3 Helix-loop-helix family factors 6
1-6 Non-Smad signaling in TGF-β-induced EMT 7
1-7 Head and Neck Cancer 7
2. Microtubule-targeted anticancer drugs 8
Specific aims 9
Materials and Methods 10
1. Chemicals and antibodies 10
2. Cell lines and culture conditions 10
3. Cell viability assay 11
4. Western blot analysis 11
5. Invasion assay 11
6. Wound healing assay 12
7. Immunofluorescent analysis of F-actin 12
8. RT-PCR 12
9. Hypoxia inducible factor 1 alpha (HIF-1α) knockdown 13
10. Statistical Analysis 13
Results 14
1. Anti-proliferative activity of microtubule inhibitors in OEC-M1 cells 14
2. The effect of MPT0B098 on hypoxia-induced EMT process in OEC-M1 cells 14
3. MPT0B098 is more potent than other microtubule inhibitors to inhibit the expression of EMT-related protein 14
4. Hypoxia promotes migration and invasion of OEC-M1 cells 15
5. MPT0B098 inhibits cell migration and the expression of F-actin and p-FAK under hypoxic-condition 16
6. MPT0B098 does not affect the invasion of OEC-M1 cells 17
7. MPT0B098 down-regulates TGF-β-induced phosphorylation of receptor-associated Smads by decreasing TGF-β mRNA and protein levels 17
8. HIF-1α knockdown causes no effect on TGF-β-induced phosphorylation of receptor-associated Smads in OEC-M1 cells 18
9. The inihbitory effect of MPT0B098 on TGF- β-induced Smad signaling under a normoxia condition 19
Discussion 21
References 24

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