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系統識別號 U0026-0908201219005300
論文名稱(中文) 磷酸化Prohibitin調控癌轉移之研究
論文名稱(英文) Phosphorylated Prohibitin Regulates Cancer Metastasis
校院名稱 成功大學
系所名稱(中) 生物科技研究所碩博士班
系所名稱(英) Institute of Biotechnology
學年度 100
學期 2
出版年 101
研究生(中文) 邱慶豐
研究生(英文) Ching-Feng Chiu
學號 l68931134
學位類別 博士
語文別 英文
論文頁數 122頁
口試委員 召集委員-吳金洌
口試委員-陳宗嶽
口試委員-洪健睿
口試委員-郭呈欽
口試委員-謝政哲
指導教授-楊淑美
中文關鍵字 prohibitin  Raf  Akt  rVP1  磷酸化  癌轉移 
英文關鍵字 prohibitin  Raf  Akt  rVP1  phosphorylation  cancer metastasis 
學科別分類
中文摘要 癌症一直高居台灣十大死亡的第一位,而癌轉移是造成九成罹癌致死的主要因素。如何有效預防、檢測及治療癌症一直是重要的公共衛生議題及醫學研究的重點。實驗室利用抗癌蛋白(VP1)於癌細胞中尋找出Prohibitin(PHB)蛋白,進一步發現細胞膜上PHB蛋白與臨床上癌症的分期是有正相關性的,而且細胞膜上PHB蘇胺酸258及酪胺酸259的磷酸化程度更與癌細胞侵犯能力有著密切的關係。在體外細胞試驗中,當經由PI3K/Akt磷酸化細胞膜上PHB會促進細胞的移動和侵犯能力並且活化細胞內Raf-1/ERK訊息傳遞,同時亦會增強細胞在上皮-間質型態上的轉變(epithelial-mesenchymal transition, EMT)並活化基質金屬蛋白酵素-2而增強癌細胞侵犯能力。利用免疫沉澱法證實磷酸化PHB經由與Raf-1、Akt及Ras蛋白在細胞膜上的結合作用,而有助於Ras誘導Raf-1的訊息傳遞。進一步於動物試驗中,比較有接種大量表現細胞膜上PHB之癌細胞在小鼠原位子宮頸與對照組,顯示其原位腫瘤有明顯增大及癌細胞轉移的現象進而縮短小鼠的存活時間。利用定點突變方法使PHB上蘇胺酸258及酪胺酸259失去磷酸化作用,於體外細胞及動物試驗中,亦證實磷酸化PHB對於癌細胞在轉移上會有所影響。此外,利用抗癌蛋白rVP1經由抑制integrin/PI3K/Akt來降低PHB蘇胺酸258的磷酸化,亦會影響磷酸化PHB和Raf-1的結合能力而降低Raf-1/ERK訊息傳遞,於體外細胞及動物試驗中能抑制癌細胞的轉移。這些實驗結果預期磷酸化PHB不但具有潛力可以作為臨床上檢測癌細胞轉移程度的指標,亦可當作尋找抗癌轉移藥物之目標物。
英文摘要 Cancer is the leading cause of death in Taiwan, and cancer metastasis remains the cause of 90% of human cancer deaths. The effective prevention, detection and treatment of cancer have been an important public health issue and the focus of medical research. We used an anti-cancer protein (rVP1) to treat cancer cells and found prohibitin (PHB) protein might regulate and involve in cancer progression. Moreover, we found a positive correlation between plasma membrane PHB and the clinical stages of cancer. The level of plasma membrane PHB which phosphorylated at threonine 258 (T258) and tyrosine 259 (Y259) correlated with the invasiveness of cancer cells. Overexpression of PHB in plasma membrane enhanced cell migration/invasion through Raf-1/ERK activation. It also enhanced EMT, MMP-2 activity and invasiveness of cancer cells in vitro. Immunoprecipitation analysis demonstrated that phospho-PHB associated with Raf-1, Akt and Ras in the membrane and was essential for the activation of Raf-1 signaling by Ras. Mice implanted with cancer cells stably overexpressing PHB in plasma membrane showed enlarged cervical tumors, enhanced metastasis and shorter survival time. Dephosphorylation of plasma membrane PHB at T258 and T259 diminished the in vitro and in vivo effects of PHB. In addition, treatment of rVP1 decreased the level of phospho-PHB at T258 through integrin/PI3K/Akt signaling and the association of phospho-PHB with Raf-1. As a result of this loss of interaction of PHB/Raf-1, there was reduced phosphorylation of Raf-1 and its downstream ERK, and suppression of cancer metastasis in vitro and in vivo. These results suggest that the phospho-PHB may thus serve as not only a potential marker for cancer metastasis but also a target for screening anti-metastatic agents.
論文目次 致謝......................................................I
Table of Contents........................................II
List of Figures...........................................V
Abbreviations.............................................X
Abstract.................................................XI
摘要.....................................................XII

Chapter 1. Introduction....................................1
1.1. Literaure Review......................................1
1.2. Specific Aims........................................11

Chapter 2. Materials and Methods..........................19
2.1. Materials............................................19
2.2. Cell lines...........................................20
2.3. Construction of plasmids.............................20
2.4. siRNAs and transfection procedures...................21
2.5. Fluorescence histochemistry for detection of membrane-bound PHB in human cervical cancer tissues................21
2.6. Flow cytometric analysis.............................23
2.7. Purification of recombinant VP1 protein..............23
2.8. Cell viability assay.................................24
2.9. Clonogenic assay.....................................25
2.10. Cell migration and invasion assay...................25
2.11. Gelatin zymographic analysis........................26
2.12. Isolation of plasma membrane proteins...............26
2.13. Isolation of membrane raft proteins.................26
2.14. Isolation of plasma membrane domains................27
2.15. Measurement of PIP3 amount by ELISA.................28
2.16. Immunoprecipitation, pull-down assay and western blotting..................................................28
2.17. Establishment of stable cell lines of HeLaD-GFP, HeLaD-PHB-GFP, HeLaD-PHB-GFP(T258I), HeLaD-PHB-GFP(Y259F) and HeLaD-PHB-GFP(T258I/Y259F)............................29
2.18. Establishment of a human cervical cancer xenograft model with lung metastasis................................29
2.19. Establishment of an orthotopic human cervical cancer xenograft model in SCID mice..............................30
2.20. Immunohistochemistry................................30
2.21. Extraction of tissue proteins.......................31
2.22. Extraction of formalin-fixed paraffin-embedded (FFPE) tissue proteins...........................................31
2.23. Histopathology examination..........................32
2.24. Animal care.........................................32
2.25. Statistical analysis................................32

Chapter 3. Plasma Membrane PHB Associates with Cell Invasion and Cancer Metastasis............................42
3.1. Introduction.........................................42
3.2. Results..............................................43
3.3. Discussion...........................................48

Chapter 4. Phosphorylation of Plasma Membrane PHB Regulates the Metastatic Progression of Cancer Cells................68
4.1. Introduction.........................................68
4.2. Results..............................................69
4.3. Discussion...........................................74

Chapter 5. Phosphorylated PHB Is a Target to Suppress Tumor Growth and Cancer Metastasis..............................91
5.1. Introduction.........................................91
5.2. Results..............................................91
5.3. Discussion...........................................95

Chapter 6. General Conclusion............................108

References...............................................109
自述.....................................................118
Appendix.................................................119
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