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系統識別號 U0026-1408201315580400
論文名稱(中文) RON酪胺酸激酶在缺氧狀態下入核活化非同源黏合系統去氧核糖核酸修補之研究
論文名稱(英文) Activation of Non-Homologous End Joining (NHEJ) DNA Repair by Nuclear Translocation of RON in Cancer Cells under Hypoxia
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 101
學期 2
出版年 102
研究生(中文) 張庭嘉
研究生(英文) Ting-Chia Chang
學號 t16001045
學位類別 碩士
語文別 中文
論文頁數 64頁
口試委員 指導教授-周楠華
口試委員-黃溫雅
口試委員-顏家瑞
中文關鍵字 酪胺酸激酶  缺氧  非同源黏合系統 
英文關鍵字 RTK  HYPOXIA  NHEJ 
學科別分類
中文摘要 RON酪胺酸激酶在缺氧狀態下入核活化非同源黏合系統去氧核糖核酸修補之研究
研究生:張庭嘉 指導老師:周楠華
背景:
微環境中營養缺乏、缺氧甚至酸鹼值的改變可以調控並促進癌細胞生長。癌細胞為了對抗或躲避如此惡劣的環境,會發展出一系列的保護機制,以便對付營養缺乏或是缺氧的壓力。本研究主要是要探討癌細胞如何逃脫此惡劣環境。RON 酪胺酸激酶是c-Met 致癌基因家族的成員,正常的位置是在細胞膜上,並接受配體刺激活化下游的路徑。然而,先前我們的研究指出:在營養缺乏的環境下,RON受體會與表皮成長因子受體(EGFR)結合,一起進入細胞核內,扮演轉錄調控因子的角色(Carcinogenesis, 2010)。我們最近的研究也發現,TSGH8301膀胱癌細胞株在缺氧環境下,RON受體也會有入核的現象。為了想要了解RON受體入核後會與哪些蛋白作用,我們將膀胱癌細胞株經缺氧處理後,收集細胞核的萃取液,利用RON的抗體進行免疫沉澱,並將樣本送交至高效液相質譜儀(HPLC-MS/MS)進行分析。在鑑定出的80個蛋白中,我們選取Ku70和DNA-PKcs進行下列的實驗。
假設:
癌細胞在缺氧的情形下,進入細胞核內的RON受體,可能可以活化非同源黏合系統(NHEJ),進行去氧核糖核酸修補的作用。
目的:
(1) 探討膀胱癌細胞在缺氧的環境下,雙股斷裂的偵測與修補蛋白的表現
(2) 探討膀胱癌細胞在缺氧的環境下,RON、Ku70與DNA-PKcs的關係
(3) 探討膀胱癌細胞在缺氧後,進入細胞核內的RON 在非同源黏合系統去氧核糖核酸修補中扮演的角色

(4) 探討膀胱癌細胞在缺氧後與處理抗癌藥物後,對缺乏RON表現的癌細胞的影響
結果:
在處理缺氧或是抗癌藥物後,DNA受損偵測蛋白(p-ATM、rH2AX)表現量有顯著的上升;但DNA修補蛋白(Ku70、DNA-PKcs)表現沒有差異。不過代表非同源黏合修補系統的磷酸化DNA-PKcs,會隨著缺氧時間增加而上升。在處理缺氧或是抗癌藥物後,細胞核內的RON、Ku70與DNA-PKcs會交互作用。進一步研究發現,在缺氧環境下,RON的激酶結構區(kinase domain)與Ku70會結合。隨著缺氧的時間增加,膀胱癌的非同源黏合修補系統表現也會上升。我們並發現,RON穩定表現的癌細胞生長的較好。缺少RON表現的癌細胞對於雙股斷裂的抗癌藥物敏感性較高。
結論:
由缺氧或是抗癌藥物造成的DNA雙股斷裂,原先在細胞膜上的RON會移動至細胞核內,與Ku70、DNA-PKcs交互作用,並活化非同源黏合修補系統,發揮保護RON表現癌細胞的功能。
英文摘要 Activation of Non-Homologous End Joining (NHEJ) DNA Repair by Nuclear Translocation of RON in Cancer Cells under Hypoxia
Student: Ting-Chia Chang Advisors: Nan-Haw Chow
Background:
Cancer progression is modulated by alterations of microenvironment, such as nutrient starvation, hypoxia and pH change. To survive under these harsh conditions cancer cells must undergo a series of modifications to overcome the O2- and/or nutrient-deprived stresses. Receptuer d'Origine Nantatise (RON) is a member of c-Met RTK family and requires its cognate ligand in activating the downstream pathways. We have reported that membranous RON receptor, in association with epidermal growth factor receptor, could be transported to the nucleus of cancer cells and acts as a transcriptional regulator in response to serum starvation. Recently, we also demonstrated the nuclear translocation of RON when TSGH8301 bladder cancer cells are exposed to hypoxia. To identify its nuclear targets, nuclear fraction was co-immunoprecipitated (Co-IP) with RON antibody, fractionated by high performance liquid chromatography, and submitted for tandem mass analysis (Co-IP-HPLC- MS/MS). Among 80 candidate proteins, both Ku70 and DNA-PKcs were chosen for further investigation.
Hypothesis:Modulation of NHEJ repair by nuclear RON may be one of machineries for cancer cells in response to hypoxic stress.
Specific aims:
(1) To examine the expression of double strand break (DSB) sensor and repair proteins under hypoxia
(2) To investigate the relationship between RON and Ku70/DNA-PKcs complex under hypoxia
(3) To investigate the role of nuclear RON in NHEJ repair under hypoxia
(4) To examine the chemosensitivity of RON-knockdown stable cells in vitro under hypoxia
Results:
We found an up-regulation of DNA sensor proteins, i.e. p-ATM, γ-H2AX, under hypoxia, while expression of Ku70 and DNA-PKcs remained unchanged. However, there is time-dependent up-regulation of phospho-DNA-PKcs under hypoxia. On the other hand, expression of γ-H2AX was inhibited by DNA-PK inhibitor (NU7026) under hypoxia for 6 and 24 hr, respectively. The interaction of RON with Ku70 and DNA-PKcs in the nuclear fraction was confirmed by Co-IP of total or nuclear fraction of TSGH8301 cells and confocal microscopy. Domain mapping experiments using HEK293 cells co-transfection suggest that kinase domain of RON is essential for its interaction with Ku70 under hypoxia. The end-joining assay showed an activation of NHEJ repair by nuclear RON under hypoxia. Besides, we also demonstrated interaction of nuclear RON with Ku70/DNA-PKcs complex after treatment with DSB-inducing anticancer drugs. The RON-knockdown stable cells are more sensitive to hypoxic stress or chemotherapy treatment in vitro.
Conclusions:
1. When bladder cancer cells are exposed to hypoxic stress, nuclear translocation of RON interacts with Ku70 and DNA-PKs to activate the NHEJ repair.
2. The DSB inducing anti-cancer drugs also initiates nuclear translocation of RON and its interaction with Ku70/DNA-PK complex.
論文目次 Contents
Abstract in English I
Abstract in Chinese III
Acknowledgements V
Contents VI
Index of Tables IX
Index of Figures X
Introduction
-Bladder cancer………………………………………………………..…1
-RTK (Receptor tyrosine kinase)………………………………..……….2
-RON……………………………………………………………………..3
-Hypoxia………………………………………………………………….5
-NHEJ (non-homolog end joining) repair………………………...…….6
-Chemotherapy resistance………………………………………..….......8
Material and Methods
-Cell lines……………………………………………………………….10
-Chemicals……………………………………………………………...10
-Constructs……………………………………………………………...10
-Construction of Ku70………………………………………………….11
-Mini preparation……………………………………………………….11
-Midi preparation……………………………………………………….11
-Transfection……………………………………………………………12
-Western blot (WB)……………………………………………………..12
-Cellular fractionation………………………………………………….13
-Co-immunoprecipitation (Co-IP)……………………………………..14
-3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) Assay…………………………………………………………………….14
-Immunofluorescent assay (IFA)………………………………………14
-Plasmid end-joining assay…………………………………………….15
-Immunohistochemistry………………………………………………..15
-Anti-cancer drugs……………………………………………………...16
Results
Search for target proteins of nuclear RON under hypoxia………………………………………………………………….17

Objective 1:Hypoxic stress
Activation of DNA DSB and repair system during hypoxia…………..17
Interaction of nuclear RON with Ku70/ DNA-PKcs complex under hypoxia………………………………………………………………….18
Domain mapping of RON responsible for interaction with Ku70…………………………………………………………………….19
Activation of NHEJ repair by nuclear RON under hypoxia………….19

Objective 2:Anti-cancer drugs (double strand break damage)
Impact of RON/Ku70/DNA-PKcs complex upon chemosensitivity in vitro……………………………………………………………………...20
The chemosensitivity of RON-knockdown stable cells in vitro under hypoxia………………………………………………………………….21
Discussion………………………………………………………………23
References………………………………………………………………26

Index of Tables
Table 1: Proteins associated with nuclear RON identified by IP-HPLC- MS/MS………………………………………………………………34

Index of Figures
Figure 1:Subcellular distribution of RON in TSGH8301 cells in response to hypoxia (contributed by Hong-Yi Chang)……………...…37
Figure 2:The diagram of target protein hunting for nuclear RON under hypoxia…………………………………………………………..38
Figure 3:Expression of γH2AX in relation to hypoxic exposure……39
Figure 4:Expression of HIF-1α in relation to hypoxic exposure………………….......................................................................40
Figure 5:The significance of DNA-PKcs on γH2AX expression under hypoxia………………………………………………………………….41
Figure 6:Reactive oxygen species (ROS) production by mitochondria is induced by hypoxia initiated and its effect on DNA damage………………………………………………………………….42
Figure 7: Expression of DNA damage sensor and repair proteins in response to hypoxia…………………………………………………….43
Figure 8:Expression of phospho-DNA-PK in response to hypoxia……………….............................................................................44
Figure 9:Interaction of RON with Ku70 and DNA-PKcs under hypoxia………………………………………………………………….45
Figure 10:Interaction of nuclear RON with Ku70 and DNA-PKcs in nuclear fraction………………………………………………………...46
Figure 11:Confocal microscopy of nuclear RON with Ku70 under hypoxia…….............................................................................................47
Figure 12:Confocal microscopy of nuclear RON with DNA-PKcs under hypoxia…………………………………………………………..48
Figure 13:This diagram of the truncated domains of RON protein…………………………………………………………………..49
Figure 14:The construct of Ku70 protein and its protein expression…………….............................................................................50
Figure 15:Kinase domain mapping of RON responsible for interaction with Ku70……………………………………………………………….51
Figure 16:DNA-PK activity in relation to RON expression under hypoxia………………………………………………………………….52
Figure 17:Measurement of NHEJ repair capability in relation to hypoxia………………………………………………………………….53
Figure 18:The growth kinetics of TSGH8301-vector and KD-RON stable cells under hypoxia……………………………………………...54
Figure 19:Immunolocalization of RON and Ku70 expression in primary bladder cancer in relation to blood vessel……………………55
Figure 20:Expression of DNA damage sensor and repair proteins after treatment with DSB-inducing anti-cancer drugs……………………...56
Figure 21:Interaction of RON with Ku70 and DNA-PKcs after treatment with DSB drugs……………………………………………...57
Figure 22:Confocal microscopy of RON with Ku70 after treatment with DSB- inducing drugs…………………………………………………...59
Figure 23:The impact of RON expression on cell survival after treatment of DSB-inducing drugs……………………………………...61
Figure 24:The impact of RON expression on cell survival under hypoxia after treatment with DSB-inducing drugs……………………63
Figure 25: The impact of RON expression on survival of J82 stable cells in the presence of epirubicin under normoxia or hypoxia………64
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