一、利用蛋白質體學探討氧化壓力、抑制Src激酶和榭黃素對大鼠心肌細胞的影響:建立心臟缺血再灌流以及治療的細胞模組二、利用蛋白質體學分析可利用於疾病中的生物標記蛋白

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研究生：	陳依玟 Chen, Yi-Wen
論文名稱：	一、利用蛋白質體學探討氧化壓力、抑制Src激酶和榭黃素對大鼠心肌細胞的影響:建立心臟缺血再灌流以及治療的細胞模組二、利用蛋白質體學分析可利用於疾病中的生物標記蛋白 Ⅰ. Proteomics study of oxidative stress, Src kinase inhibition and quercetin in H9C2 cardiomyocytes: a cell model of heart ischemia reperfusion injury and treatment Ⅱ. The application of proteomics for disease biomarker discovery and mechanism study
指導教授：	詹鴻霖 Chan, Hong-Lin
口試委員:	王慧菁 Lily Wang 張建文 Chang, Chein-Wen 王浩文 Wang, Hao-Ven 周秀專 Chou, Hsiu-Chuan
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生物資訊與結構生物研究所 Institute of Bioinformatics and Structural Biology
論文出版年：	2014
畢業學年度：	103
語文別：	英文
論文頁數：	188
中文關鍵詞：	蛋白質體學、蛋白質磷酸化、缺血再灌流傷害、榭黃素、大鼠心肌細胞、氧化壓力、肢體末梢缺血、糖尿病、移行性膀胱癌、氧化還原蛋白質體學、子宮肌瘤癌、健擇、胰臟癌、乳癌、粒線體
外文關鍵詞：	Proteomics, Protein phosphorylation, Ischemia-repurfusion injury, Quercetin, H9C2 cardiomyocyte, Oxidative stress, Critical limb ischemia, Diabetic, Transition carcinoma cancer, Redox proteomics, Uterine leiomyoma, Gemcitabine, Pancreatic cancer, Breast cancer, Mitochondria
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PART І. 利用蛋白質體學研究大鼠心肌細胞在氧化壓力、酪氨酸激酶抑制子以及榭黃素的影響: 建立心臟缺血再灌流和治療的細胞模型
心肌缺血再灌流的氧化壓力傷害，容易藉由蛋白質磷酸化的變化來調控基因之表現和代謝，進而影響細胞貼附與存活能力。在本研究中，受到過氧化氫刺激後的大鼠心肌細胞是用來當作心臟缺血再灌流所導致傷害的細胞模組，且經由氧化壓力刺激細胞後，細胞內的蛋白質上產生大量磷酸化的酪胺酸。所以，為了純化氧化壓力所誘導的酪胺酸磷酸化蛋白，我們使用親和性樹脂來得到酪胺酸磷酸化蛋白質，進而利用液相串聯式質譜儀來鑑定磷酸化酪胺酸蛋白質。根據質譜儀分析結果發現約23種蛋白質其功能參與細胞間傳遞、維持細胞骨架以及細胞貼附能力；由此可知，氧化壓力對於細胞貼附能力，型態和存活影響甚鉅，經由STRING網站分析得知Src激酶為這些蛋白質的上游調控者。進一步研究發現，我們利用免疫螢光染色法、螢光偵測流式細胞儀和細胞貼附計數法來證實過氧化氫致使細胞不具貼附能力並走向凋亡，然而前處理固定量的PP1或榭黃素後可保護過氧化氫對細胞所造成的傷害。而榭黃素透過抑制STAT3活性來阻礙過氧化氫所導致細胞發炎反應，藉此有效避免心肌細胞受到缺血再灌流的傷害。綜合以上結果，在氧化壓力下所誘導蛋白質磷酸化以及細胞傷害中Src激酶扮演著重要角色，並且使用Src激酶的抑制劑以及榭黃素可有效避免心臟因缺血再灌流所導致的傷害。

PART П. 利用蛋白質體學分析可利用於疾病中的生物標記蛋白
在現今社會裡，糖尿病和癌症的發生是相當普遍且為國人十大死因。早期疾病的發現、手術治療與術後治療可以提升疾病患者存活率。在本論文中，收集代謝性疾病裡包含糖尿病引起的肢體末梢缺血、第一型糖尿病、或移行性膀胱癌和子宮肌瘤病患的血清，進而利用螢光標定二維電泳結合基質輔助雷射脫附游離飛行質譜儀來分析鑑定，並找出相關生物標記蛋白質。從本研究中，特定疾病血清中具有其高度表現的特有生物標記蛋白，例如糖尿病引法末梢肢體缺血病患中所引發的DAPP1、第一型糖尿病患中的血紅素、膀胱癌病患中的硒半胱胺酸專一的延長因子和子宮肌瘤患者中的維生素D鍵結蛋白；特別的是，在第一型糖尿病患中，血紅素呈現氧化狀態。但是大部分鑑定出來的血清蛋白幾乎都和免疫反應以及血液凝結相關的常見蛋白質。為了避免這些血清在血清中大量蛋白質的干擾，所以我們利用細胞來找尋生物標記蛋白。在本論文中，使用胰臟癌細胞和乳癌細胞來尋找關於引發抗藥性和癌化的生物標記蛋白。在gemcitabine所誘導的抗藥性胰臟癌細胞裡含有大量核糖核苷二磷酸還原酶而且胰臟癌抗藥性的發生可能和腫瘤抑制子p53有關，而在高度癌化的乳癌細胞中，粒腺體大量表現出鈣結合線粒體載體蛋白SCaMC-1，進一步，SCaMC-1被證實在乳癌病患血清中也有較高含量。從此論文得知，從血清中找尋可偵測或治療疾病的生物標記蛋白仍是相當困難，但另一方面，先從細胞平台上獲得具疾病專一性的標記蛋白質後，再進一步利用病患血清來確認哪些生物標記蛋白是可被用於疾病篩檢與治療。

PART І. Proteomics study of oxidative stress, Src kinase inhibition (PP1) and Quercetin in H9C2 cardiomyocytes: a cell model of heart ischemia reperfusion injury and treatment.
Oxidative stress production of myocardial ischemia/reperfusion injury leads to protein phosphorylation in regulating gene expression, metabolism, cell adhesion and survival. In this thesis, we used hydrogen peroxide treatment of H9C2 rat cardiomyocytes as a model of oxidative stress in heart ischemia reperfusion injury. A proteomics approach using anti-phosphotyrosine affinity purification and LC-MS/MS was then used to identify the stress-induced protein phosphorylation. We showed that oxidative stress induces a robust tyrosine phosphorylation of multiple proteins in this cell type. Most of identified tyrosine phosphorylated proteins were relative to cell-cell junctions, the actin cytoskeleton and cell adhesion. This suggested that oxidative stress may have a profound effect on intercellular connections and the cytoskeleton to affect cell adhesion, morphology and survival. After stress-induced phosphotyrosine proteins were analyzed by STRING, Src kinase was shown to be a major upstream regulator of these events. Furthermore, immunofluorescence studies, fluorescent activated cell sorting and cell-based assays were used to demonstrate H2O2-induced modifications of cell adhesion structures and cytoskeleton, de-adhesion and apoptosis, which were reversed by treatment with the Src kinase inhibitor PP1 or quercetin. Moreover, quercetin likely blocked the H2O2-induced inflammatory response through STAT3 modulation, which also contributed in preventing ischemia/reperfusion injury in cardiomyocytes. These findings provide the critical role of Src kinase in oxidative stress-induced phosphorylation and cell damage in cardiomyocytes and suggested that targeting Src kinase or quercetin may be an effective strategy for preventing ischemia reperfusion injury in the heart.

PART П. The application of Proteomics for disease biomarker discovery
Cancer and diabetic are high incidence and mortality in worldwide; however, early detection, surgical resection and postoperative therapy can lead to survival improvement for cancer or diabetes. In recent study, body fluids of patient were used to screen markers, such as plasma, urine and cerebrospinal fluid. Here, plasma of critical limb ischemia (CLI), type 1 diabetic (T1DM), transition carcinoma cancer and uterine leiomyoma were collected and analyzed by 2D-DIGE and MALDI-TOF. Then, particular protein markers were found in specific diseases, such as dual adapter for phosphotyrosine and 3-phosphotyrosine and 3-phosphoinositide (DAPP1) in CLI, hemopexin in T1DM, selenocysteine-specific elongation factor in TCC and vitamin D-binding protein in uterine leiomyoma. Nevertheless, most identified plasma proteins are related to inflammatory responses and blood coagulation. Therefore, a cell-based platform was established to screen protein markers relating to gemcitabine (GEM)-induced drug resistance pancreatic cells and tumorigenic breast cells. In GEM-induced drug resistant pancreatic cells, ribonucleoside-diphosphate reductase large subunit significantly overexpressed and tumor suppressor protein p53 may interplay with GEM-induced pancreatic cell resistance. In addition, in breast cancer cells, the level of calcium-binding mitochondrial carrier protein SCaMC-1 in tumorigenetic breast cancer cells or breast cancer patients’ plasma was higher than that of normal cell or health donors’ plasma. These data demonstrate that plasma proteomics provides a lot of common proteins between various diseases, but a cell based strategy provides a good platform for specific protein markers discovery in particular disease and afterwards these protein markers are potential for disease screening.

Overview................................................1
中文摘要.................................................2
Abstract................................................4
Abbreviations...........................................6
Part I..................................................9
Chapter 1 Introductions ...............................10
Chapter 2 Materials and Methods .......................17
2.1 Chemicals and Reagents.............................17
2.2 Cell lines, cell culture, cell treatment...........17
2.3 Immunoblotting.....................................18
2.4 Small-scale immunoprecipitation....................18
2.5 Large-scale tyrosine phosphorylated protein enrichment.............................................19
2.6 In-gel digestion...................................20
2.7 Liquid chromatography and tandem mass spectrometry.20
2.8 Immunostaining and fluorescence microscopy.........21
2.9 Adhesion assays....................................22
2.10 MTT cell viability assay..........................22
2.11 Wound healing assay...............................23
2.12 Apoptosis assay using flow cytometry..............23
2.13 Reactive oxygen species in cells were detected using DCFH-DA assay..........................................23
2.14 2D-DIGE and gel image analysis...............................................23
2.15 Protein identification by MALDI-TOF MS............25
Chapter 3 Results......................................26
3.1 Hydrogen peroxide treatment induces tyrosine phosphorylation and activation of PI3K and stress response signaling pathways in H9C2 cardiomyocyte..........................................26
3.2 Identification of hydrogen peroxide-induced tyrosine phosphorylated proteins................................27
3.3 Role of Src kinases in H2O2-induced tyrosine phosphorylation........................................28
3.4 Role of Src kinase in hydrogen peroxide-induced loss of cell adhesion and viability.........................29
3.5 Quercetin pretreatment suppresses hydrogen peroxide-induced tyrosine phosphorylation in cardiomyocytes.....31
3.6 Quercetin inhibits hydrogen peroxide-induced changes in cell morphology and loss of cell adhesion...........31
3.7 Quercetin inhibits phosphorylation of STAT3, PI3K/Akt and p38 kinase and the expression of COX-2 in H2O2-induced H9C2 cells.....................................32
3.8 Pretreatment with quercetin suppresses ROS production in H2O2-treated H9C2 cells.............................32
3.9 Quercetin reduces hydrogen peroxide-induced H9C2 cell apoptosis..............................................33
3.10 2D-DIGE analysis of untreated, H2O2-treated H9C2 cells and PP1 or quercetin pretreatment followed by treatment with H2O2....................................33
Chapter 4 Discussions..................................35
Chapter 5 Conclusions..................................43
Chapter 6 Tables.......................................44
Table 1 Proteins identified in large-scale anti-phosphotyrosine immunoprecipitation from H2O2-treated H9C2 cells.............................................45
Table 2 Alphabetic list of identified differentially expressed proteins after 2D-DIGE coupled with MALDI-TOF mass spectrometry analysis in H9C2 cells in response to H2O2 treatment and pre-treatment with PP1 or quercetin..............................................47
Chapter 7 Figures......................................49
Figure 1 Effect of hydrogen peroxide treatment on signaling in H9C2 cells and purification of tyrosine phosphorylated proteins................................50
Figure 2 MS/MS spectra of identified peptides..........51
Figure 3 Functional distribution and STRING network of the identified H2O2 -induced tyrosine phosphorylated proteins...............................................52
Figure 4 Effect of Src kinase inhibitor, PP1, on H2O2-induced signaling events and tyrosine phosphorylated protein recovery.......................................53
Figure 5 Immunofluorescence analysis of morphological and protein localization changes in H9C2 cells in response to H2O2 treatment and pre-treatment with PP1..............54
Figure 6 Effect of H2O2 and Src kinase inhibitor on H9C2 cell adhesion, viability and apoptosis.................55
Figure 7 Hydrogen peroxide treatment induces tyrosine phosphorylation in H9C2 cells..........................56 
Figure 8 Effects of quercetin on the cell morphology, migration, and adhesion of H2O2-treated H9C2 cells..................................................57
Figure 9 Effects of quercetin on the inflammatory response in H2O2-treated H9C2 cells....................59
Figure 10 Effects of quercetin on ROS production in H2O2 -H9C2 cells............................................60
Figure 11 Effects of quercetin on cell apoptosis in H2O2-treated H9C2 cells.....................................61
Figure 12 Proteomic comparison in H9C2 cells in response to H2O2 treatment and pre-treatment with PP1 or quercetin..............................................62
Figure 13 Percentage of functional distribution of differentially expressed proteins in H9C2 cell responses to H2O2 and quercetin treatment based on proteomic analysis...............................................63
Figure 14 Hypothesis model illustrating how PP1 and quercetin protects cardiomyocytes from ROS treatment...64
Part II ...............................................65
Chapter 1 Introductions..........................................66
Human plasma.................................................66
Tumor cell.............................................79
Chapter 2 Results of human plasma............73
2.1 The role of Critical Limb Ischemia in Diabetic Patients with Hemodialysis.............................73
2.2 Thiol group exchange of Hemopexin in Type I diabetic plasma.................................................75
2.3 Plasma biomarkers in Bladder transition carcinoma..............................................76
2.4 Plasma biomarkers in uterine leiomyoma.............78
Chapter 3 Discussions of human plasma..................80
3.1 Critical limb ischemia patients’ plasma proteomics.............................................80
3.2 Type I DM patients’ plasma redox proteomics........82
3.3 Bladder transition carcinoma patients’ plasma proteomics.............................................83
3.4 Uterine leiomyoma patients’ plasma proteomics.............................................84
Chapter 4 Results of tumor cell........................87
4.1 Proteomics analysis of Gemcitabine-induced drug resistance in pancreatic cancer cells..................87
4.2 Mitochondria protein markers in MCF7 and MDA-MB-231....................................................89
Chapter 5 Discussions of tumor cell....................93
5.1 Proteomic analysis of gemcitabine-induced drug resistance in pancreatic cancer cells..................93
5.2 Mitochondria proteome in MCF10A, MCF7 and MDA-MB-231....................................................96
Chapter 6 Conclusions.................................102
Chapter 7 Materials and Methods ......................104
7.1 Chemicals and Reagents............................104
7.2 Plasma samples and collection.....................104
7.3 Proteomics strategies.............................106
7.4 Cultivate Cell line...............................111
7.5 Functional assays.................................111
Chapter 8 Tables......................................114
Table 1 Clinical parameters of diabetic hemodialytic patients with / without critical limb ischemia participating in this investigation...................115
Table 2 Alphabetical list of critical limb ischemia-induced differentially expressed plasma proteins identified by MALDI-TOF peptide mass fingerprinting following 2D-DIGE analysis............................116
Table 3 Differentially labeled proteins identified by cysteine labeling 2D-DIGE and MS in T1DM.............119
Table 4 List of differentially expressed plasma proteins between bladder TCC patients (n=15) and healthy donors group (n=5) as identified by MALDI-TOF peptide mass fingerprinting following 2D-DIGE analysis.............122
Table 5 Alphabetical list of differentially expressed plasma proteins between uterine leiomyoma patients and healthy individuals as identified by MALDI-TOF peptide mass fingerprinting after 2D-DIGE analysis............124
Table 6 Alphabetical list of identified differentially expressed proteins across various levels of gemcitabine-induced drug resistant PANC-1 pancreatic cells obtained after 2D-DIGE coupled with MALDI-TOF mass spectrometry analysis.............................................126
Table 7 List for proteins potentially contributing to fatty acid synthesis, fatty acid biodegradation, protein synthesis, protein degradation, vascular transport, DNA synthesis, detoxification and calcium-dependent regulation in comparing GEM-resistant PANC-1 cells with GEM-sensitive PANCcells..............................129
Table 8 Alphabetic list of identified differentially expressed mitochondrial proteins across MCF-10A, MCF-7, and MDA-MB-231 breast cells obtained after 2D-DIGE coupled with MALDI-TOF mass spectrometry analysis.....130
Table 9 Potential proteins from identified protein list..................................................131
Chapter 9 Figures.....................................133
Figure 1 The efficiency evaluation for removal of albumin and immunoglobulin G from plasma samples.............134
Figure 2 Experimental design to perform 2D-DIGE/MALDI-TOF MS-based quantitative plasma proteomics...............135
Figure 3 2D-DIGE analysis of critical limb ischemia-induced differentially expressed proteins............136
Figure 4 Peptide finger printing of identified proteins CD5L and haptoglobin..................................137
Figure 5 Percentage of plasma proteins identified from albumin and imunnoglobulin G depleted plasma by 2D-DIGE / MALDI-TOF MS for critical limb ischemia according to their biological functions and subcellular location...138
Figure 6 Representative images of the identified spots displaying critical limb ischemia–dependent protein abundance changes....................................139
Figure 7 Representative immunoblotting analysis of haptoglobin and ELISA analysis of haptoglobin, 14-3-3 zeta and leucine-rich alpha-2-glycoprotein for selected differentially expressed plasma proteins identified by proteomic analysis in patients with and without critical limb ischemia........................................140
Figure 8 Redox 2D-DIGE analysis of type 1 diabetes mellitus-induced differential cysteine-modification in plasma...............................................141
Figure 9 Percentage of plasma proteins identified from albumin and imunnoglobulin G depleted plasma by 2D-DIGE / MALDI-TOF MS for type 1 diabetes mellitus according to their biological functions............................142
Figure 10 Validation of the thiol reactive plasma protein, hemopexin, identified through redox-proteomic study in between type 1 diabetes mellitus patients and healthy donors by immunoprecipitation.................143
Figure 11 2D-DIGE comparative analysis of plasma from bladder TCC cases and healthy controls................144
Figure 12 Peptide mass fingerprinting analysis of identified proteins by MALDI-TOF/TOF MS...............145
Figure 13 Percentage of identified differentially expressed plasma proteins between bladder TCC cases and healthy donors according to their sub-cellular locations and biological functions by 2D-DIGE / MALDI-TOF MS....146
Figure 14 Representative images of the identified spots displaying bladder TCC–dependent protein expression changes.............................................147
Figure 15 Immunoblotting and ELISA analysis of Carbonic anhydrase 1, haptoglobin, leucine-rich alpha-2-glycoprotein and actin in bladder TCC plasma and healthy control plasma........................................148
Figure 16 2D-DIGE analysis of uterine leiomyoma-induced differentially expressed proteins…....................149
Figure 17 Peptide finger printing of identified proteins..............................................150
Figure 18 Representative images of the identified spots displaying uterine leiomyoma–dependent protein expression changes...............................................151
Figure 19 Percentage of plasma proteins identified from albumin and imunnoglobulin G depleted plasma by 2D-DIGE / MALDI-TOF MS for uterine leiomyoma according to their biological functions.................................152
Figure 20 Representative immunoblotting analysis of carbonic anhydrase 1 and ELISA analysis of leucine-rich alpha-2-glycoprotein and vitamin D-binding protein for selected differentially expressed plasma proteins identified by 2D-DIGE based proteomic analysis in patients with uterine leiomyoma and healthy donors....153
Figure 21 Mascot analysis of matched peptides in native and degraded haptoglobin..............................154
Figure 22 2D-DIGE analysis of diﬀerentially expressed protein proﬁling in response to various levels of gemcitabine-induced drug resistance...................155
Figure 23 Representative images of the identified spots annexin A4 and acyl-coenzyme A synthetase displaying various levels of gemcitabine resistance-induced protein expression changes....................................156
Figure 24 Peptide mass ﬁngerprint of identiﬁed proteins..............................................157
Figure 25 Representative ELISA and immunoblotting analyses for selected diﬀerentially expressed proteins identiﬁed by proteomic analysis in various levels of gemcitabine resistant cells...........................158
Figure 26 Interaction networks of identiﬁed proteins..159
Figure 27 Analysis of purity of the mitochondrial protein extracts by immunoblotting and 2D-DIGE................160
Figure 28 Analysis of the breast mitochondrial proteomes of MCF-10A, MCF-7, and MDA-MB-231 cells by 2D-DIGE....161
Figure 29 Differential expressions of mitochondrial proteins across MCF-10A, MCF-7, and MDA-MB-231........162
Figure 30 Percentage of intracellular locations of isolated mitochondrial fractions identified by 2D-DIGE/MALDI-TOF MS for MCF-10A, MCF-7, and MDA-MB-231 cells.................................................163
Figure 31 Representative immunoblotting and immunofluorescence analysis for selected differentially expressed protein (MnSOD) identified by mitochondrial proteome analysis across MCF-10A, MCF-7, and MDA-MB-231 cells.................................................164
Figure 32 Immunoblotting and immunofluorescence analysis of the expression of SCaMC-1 across normal breast cell (MCF-10A) and various breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-453, and MDA-MB-435 cells)........165
Figure 33 ELISA analysis of plasma SCaMC-1 levels in healthy donors, breast cancer patients without metastasis, and breast cancer patients with metastasis...........................................167
Figure 34 Immunofluorescence analysis of subcellular distribution of prohibitin across MCF-10A, MCF-7, MDA-MB-453, MDA-MB-231, MDA-MB-361, MDA-MB-435, and SKBR3 cells.................................................168
Figure 35 Model of GEM-induced PANC-1 resistance......169
References............................................170
Appendix..............................................185
Publication list .....................................185 

                                

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