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系統識別號 U0026-2607201416382700
論文名稱(中文) RON在癌細胞逆境反應中所扮演的角色
論文名稱(英文) The role of receptor tyrosine kinase RON in the response of cancer cells to cellular stress
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 102
學期 2
出版年 103
研究生(中文) 張鴻議
研究生(英文) Hong-Yi Chang
學號 S58941167
學位類別 博士
語文別 英文
論文頁數 124頁
口試委員 指導教授-周楠華
召集委員-賴明德
口試委員-劉校生
口試委員-何中良
口試委員-周德盈
口試委員-洪文俊
中文關鍵字 缺氧  低氧誘導因子-1alpha  受體酪胺酸激酶  RON  DNA修補  Ku70  DNA-PK  抗藥性 
英文關鍵字 Hypoxia  HIF-1alpha  Receptor tyrosine kinase (RTK)  RON  DNA NHEJ repair  Ku70  DNA-PK  chemoresistance 
學科別分類
中文摘要 上皮細胞的癌化過程是多步驟且複雜的過程,對正常細胞而言,適應壓力所產生的反應是保護細胞的屏障之一。當癌細胞克服初始對細胞的傷害,仍會有更多苛刻的壓力陸續出現;比如養分缺乏,酸鹼度改變,缺氧等。當癌細胞建立這些壓力的耐受性時,會更加強癌化的程度。Receptuer d’Origine Nantatise (RON)是屬於c-Met 酪胺酸受體激酶家族中的一員,亦是一個致癌基因(oncogene)。我們假設:RON過度表現的癌細胞,在遭受缺氧的刺激下,RON受體蛋白會進入細胞核,與其他蛋白分子交互作用,提供癌細胞存活的能力。在這個研究我們發現,缺氧後RON會從人類膀胱癌細胞株TSGH8301的細胞膜直接進入細胞核,況且這個現象並不需要EGFR的存在。在剔除HIF-1後再進一步缺氧,我們發現即使在剔除HIF-1alpha的細胞中,RON蛋白分子也還會進入細胞核內。 我們也意外發現,在HIF-1alpha表現的細胞中,RON與HIF-1alpha依舊會產生交互作用。我們進一步證明,RON與HIF-1alpha的交互作用是透過RON的酪胺酸激酶區域。利用RON的顯性負突變使其tyrosine無法被磷酸化,酪胺酸激酶失去活性,也就無法和HIF-1alpha交互作用,顯示兩者的交互作用是需要酪胺激酶的活性。我們也證明,入核的RON與HIF-1可以分別活化c-JUN promoter,在HEK293轉染HIF-1alpha與RON時,可以加成活化c-JUN promoter的功效。進一步以ChIP-PCR實驗,證明缺氧刺激後進入細胞核的RON會結合到c-JUN promoter,並增強啟動子的活性。我們也建立了穩定表現不同RON功能性突變的細胞株,證明在缺氧環境下入核的RON可以加速細胞的生長,存活,移動以及致癌性。進一步萃取缺氧後TSGH8301細胞的細胞核,在與RON的抗體進行免疫沉澱,結合高效率液相層析法分離與質譜分析,來找尋可能與RON交互作用的蛋白。我們發現了Ku-70、 DNA-PK和DNA修補有關的蛋白質。首先,我們證明缺氧會增加 gamma-H2AX, 磷酸化的ATM與DNA-PK的表現,並活化非同源末端連接DNA的修補能力。RON會參與DNA-PK磷酸化H2AX蛋白。共軛焦顯微鏡觀察與免疫沉澱兩種研究都證明,缺氧後進入細胞核的RON會與Ku70和DNAPK產生交互作用,而且需要酪酸激酶的功能性區域。另外,剔除RON表現的細胞,在預先處理Doxotubicin, Epirubicin與Mitomycin C後,在缺氧的環境下,剔除RON的癌細胞存活率會顯著的下降。同時,在這三個藥物處理下,RON會和Ku70/DNA-PK形成複合體而產生交互作用。這些結果顯示,RON入核後會與Ku70/DNAPK形成蛋白複合體,參與雙股DNA斷裂所引起的DNA修補。綜合上述所述,人類膀胱癌細胞株在缺氧環境下,RON蛋白分子會進入細胞核,與HIF-1alpha或Ku70/DNAPK交互作用,進而導致c-JUN promoter或DNA修補系統的活化。解開這些RON參與的保護癌細胞機制,可以做為未來設計抗癌藥物治療策略的重要因素。
英文摘要 Epithelial carcinogenesis is a complex, multistep process that entails the progressive acquisition of alterations to survive within rigorous microenvironment, such as hypoxia, nutrient starvation and changes in pH. Receptuer d’Origine Nantatise (RON) is a member of the c-Met RTK family. Based on its response to starvation stress, we hypothesized that RON receptor protein can translocate into nucleus of cancer cells and functions as a stress-responsive regulator for cell survival. Experiments in vitro showed that full-length RON translocates into nucleus of TSGH8301 bladder cancer cells as early as 3 hr after hypoxia and is independent of EGFR. Transient knock-down of HIF-1alpha did not disturb the nuclear translocation under hypoxia. The interaction of nuclear RON with HIF-1alpha could be demonstrated in vivo. Domain mapping revealed that tyrosine kinase truncation (RONdeleteTyrK) abolishes the interaction of RON with HIF-1alpha; while transmembrane domain deletion (RONdeleteTM) enhances the interaction of RON with HIF-1alpha and is localized in the nucleus. The luciferase promoter assay showed that RON and HIF-1alpha synergistically transactivate the c-JUN promoter. Both knockdown and putative binding-site mutation experiments demonstrated that nuclear RON seems more important than HIF-1alpha for activating c-JUN promoter, which leads to increased cell proliferation (p < 0.001), survival adaptation (p < 0.01) and migration (p < 0.001) in vitro, and tumorigenicity in vivo during hypoxia. Co-immunoprecipitation and subcellular fractionation experiments verified the interaction of nuclear RON with Ku70 and DNA-PK after hypoxia for 3, 6, 12 and 24 h, respectively. Stable cells with over-expression of RON had a higher survival rate than transmembrane truncated RON after treatment with Epirubicin within two dose ranges (0.56 and 1.125 uM) (p < 0.05). Cancer cells with over-expression of RONFL or RONdeleteTM had a better survival in the presence of Epirubicin under hypoxia than that seen under normoxia (p < 0.05, respectively). These results suggest that nuclear translocation of RON occurs in response to hypoxia in human bladder cancer cells, and is associated with HIF-1alpha, Ku70 and DNA-PK, leading to activation of c-JUN promoter activation of non- homologous end joining DNA repair. Elucidation of the mechanisms underlying nuclear RON may help to develop a novel co-targeting strategy for cancer patients with over-expression of RON.
論文目次 Table of Contents
Chinese Abstract I
Abstract II
Acknowledgment III
Table of Contents IV
List of Tables VIII
List of Figures IX
List of Appendixes XI
Abbreviation List XII
Chapter 1 Introduction 1
1.1 Human cancer 1
1.1.1 Overview of tumor biology 1
1.1.2 Oncogenes and tumor suppressor genes 2
1.1.3 Treatment in cancer therapy 3
1.2 Receptor tyrosine kinase (RTK) in human cancer 4
1.2.1 RTK superfamily 5
1.2.2 RON as a member of c-Met family 5
1.2.3 Conventional signaling pathway 6
1.2.4 Nuclear translocation of RTKs 7
1.2.4.1 Nuclear EGFR 8
1.2.4.2 Nuclear RON 8
1.2.4.3 Others examples of nuclear RTKs 9
1.3 Transcriptional regulation by nuclear RTKs 9
1.3.1 Target genes of nuclear RTKs 10
1.3.1.1 Directly regulate gene expression by nuclear RTKs 10
1.3.1.2 Indirectly regulate gene expression by nuclear RTKs 11
1.3.2 Regulatory mechanisms of nuclear RTKs 11
1.3.2.1 Nuclear EGFR 12
1.3.2.2 Nuclear RON 12
1.4 Cellular stress and cancer 13
1.4.1 Serum starvation 14
1.4.2 Hypoxia 15
1.4.3 Oxidative stress 17
1.5 DNA damage and repair in cancer 17
1.5.1 DNA double strand break 18
1.5.2 The NHEJ repair pathway 19
1.5.3 Hypoxia and double strand break 20
1.6 Objectives, hypotheses and specific aims 20
Chapter 2 Materials and Methods 22
2.1 Cell culture, passaging, seeding and hypoxia chamber 22
2.2 Chemicals and anti-cancer drugs 22
2.3 Immunohistochemical staining (IHC), immunofluorescence staining and confocal microscopy 23
2.4 Western blot analysis 24
2.4.1 Total protein extraction 24
2.4.2 Nuclear and Non-nucleus fractionation 25
2.4.3 Immunoprecipitation 25
2.4.3.1 Endogenous antigen 26
2.4.3.2 Exogenous tag protein 26
2.5 Cloning 26
2.5.1 Functional domain truncation mutants of RON 26
2.5.2 Tyrosine kinase domain construction 28
2.5.3 Dominant negative mutants of RON 28
2.5.4 Suppression constructs of RON or EGFR by miRNA 28
2.5.5 Predicting putative binding sites for RON in the c-JUN promoter 29
2.5.5.1 Serial deletion mutants of c-JUN promoter 29
2.5.5.2 Mutagenesis the putative RON binding sites 30
2.5.6 Ku70 construction 30
2.6 Transient transfection of plasmids into mammalian cells 31
2.6.1 Overexpression or luciferase report assay 31
2.6.2 Knockdown experiment 31
2.7 Generation of stable clones 32
2.7.1 Overexpression of RON mutants 32
2.7.2 Suppression of EGFR or RON expression 32
2.8 Luciferase report assay 32
2.9 Chromatin immunoprecipitation (ChIP) and ChIP-PCR 33
2.10 Cell proliferation, clonogenic and transwell assay 34
2.11 HPLC-MS/MS spectrometry 34
2.12 Plasmid end-joining assay 35
2.13 Animal experiments in vivo 36
2.14 Human bladder cancer tissue examination 36
2.15 Statistical analysis 36
Chapter 3 Results 37
3.1 Nuclear translocation of RON interacts with HIF-1α in response to hypoxia 37
3.1.1 The kinetics of the subcellular distribution of RON under normoxia and hypoxia 37
3.1.2 Subcellular distribution of RON in hepatocellular and colon cancer cells 37
3.1.3 Nuclear translocation of RON during hypoxia is independent of EGFR 38
3.1.4 Nuclear translocation of RON during hypoxia does not require HIF-1 38
3.1.5 Interaction of nuclear RON with HIF-1α in response to hypoxia 39
3.1.6 The interaction of HIF-1α with nuclear RON is dependent on the tyrosine kinase domain 40
3.1.7 Transactivation of c-JUN promoter activity by the nuclear RON and HIF-1 complex 41
3.1.8 Co-operation of nuclear RON with HIF-1 in the activation of the c-JUN promoter in a hypoxic environment 42
3.1.9 Biological functions of nuclear RON during hypoxia 44
3.1.10 The nuclear RON in xenograft experiments and human bladder cancer tissue 45
3.1.11 A hypothetical model of the nuclear translocation of RON in response to cellular stress 46
3.2 The effect of nuclear RON on DNA repair during hypoxia 46
3.2.1 Activation of DNA DSB and repair during hypoxia 46
3.2.2 End-joining activity was suppressed by knockdown of RON 47
3.2.3 γ-H2AX is regulated by phosphor-DNA-PKcs during hypoxia 48
3.2.4 Interaction of nuclear RON with DNA-PK/Ku70 complex 48
3.2.5 Domain mapping for interaction of nuclear RON with Ku70 and DNA-PK 48
3.2.6 Activation of DNA DSB and repair by nuclear RON after treatment with anti-cancer drugs 49
3.2.7 The biological implication of nuclear RON being induced by anti-cancer drugs under hypoxia 49
3.2.8 Survival advantage of RON mutants after Epirubicin treatment 50
3.2.9 Clinical implications of nuclear translocation of RON in response to chemotherapy 51
Chapter 4 Discussion 52
4.1 Interaction of nuclear RON with HIF-1α during hypoxia 52
4.1.1 Hypoxia is an important stress triggering nuclear translocation of RON 52
4.1.2 Nuclear translocation of RON is EGFR-independent during hypoxia 53
4.1.3 Interaction of nuclear RON with HIF-1 during hypoxia 53
4.1.4 Tyrosine kinase domain of RTKs is critical for protein-protein interaction 54
4.1.5 Regulation of the c-JUN promoter by nuclear RON 55
4.1.6 Biological functions of nuclear RON under hypoxia 57
4.2 Nuclear RON participates in NHEJ DAN repair during hypoxia 57
4.2.1 Hypoxia induces DSB damage and repair 58
4.2.2 Nuclear RTK participates in NHEJ repair through interaction with the DNA-PK/Ku70 complex. 59
4.2.3 Anti-cancer drugs activate nuclear translocation of RON and interaction with the Ku70/DNA-PK complex for cell survival. 60
4.2.4 Clinical implications in cancer therapy 60
Chapter 5 Conclusions 61
References 62
Tables 78
Figures 80
Appendix 117
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