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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/48124完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 阮雪芬(Hsueh-Fen Juan) | |
| dc.contributor.author | Po-Yu Hu | en |
| dc.contributor.author | 胡伯宇 | zh_TW |
| dc.date.accessioned | 2021-06-15T06:46:47Z | - |
| dc.date.available | 2011-07-06 | |
| dc.date.copyright | 2011-07-06 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-06-15 | |
| dc.identifier.citation | 1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108.
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Expression profiling of fecal colonocytes for RNA-based screening of colorectal cancer. Int J Oncol 2007;31:1029-37. 157. Shen D, Chang HR, Chen Z, He J, Lonsberry V, Elshimali Y, Chia D, Seligson D, Goodglick L, Nelson SF, Gornbein JA. Loss of annexin A1 expression | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/48124 | - |
| dc.description.abstract | 本研究為探討胃幽門螺旋桿菌(Helicobacter pylori, H. pylori)感染所導致的胃癌中，人類雌激素受器(estrogen receptors, ERs)相關的分子調控機制。我們首先分析8片胃癌病人胃部組織的互補去氧核醣核酸微陣列晶片(cDNA microarray)以得到幽門螺旋桿菌與胃癌發生相關資料。在諸多幽門螺旋桿菌感染相關表現不同的基因裡，共有82個基因表現達兩倍以上。經Ingenuity Pathway Analysis (IPA) 軟體分析後共有41個基因與4組癌症調控網路高度相關，其中雌激素受器扮演調控網路中重要的中心角色(crucial hub)，並調控20個癌症相關基因。以即時定量反轉錄聚合酶連鎖反應驗證幽門螺旋桿菌感染的胃癌細胞株AGS的基因表現，發現共有14個與雌激素受器相關的基因表現量達1.5倍以上。此外我們與Human Genome-wide High-affinity ERE資料庫進行比對後，建立了新的幽門螺旋桿菌感染所引發的胃癌之分子調控路徑。更進一步的實驗分析包括細胞存活試驗(MTT assay)、細胞週期分析(cell cycle analysis)、抗氧化測試 (oxidative stress resistance test)、細胞侵犯實驗(invasion assay)、西方墨點轉漬法(western blot)、以及即時定量反轉錄聚合酶連鎖反應。我們的結果顯示不論是1 nM 雌激素(estradiol)或10-5 M雌激素受體拮抗劑(estrogen receptor antagonist)法洛德(fulvestrant)均能有效減低AGS因幽門螺旋桿菌感染造成的增生、抗氧化力上升、和轉移能力。幽門螺旋桿菌會透過雌激素受器依賴(estrogen receptor dependent)的路徑使胃癌細胞生長、抗氧化、以及侵犯能力增加。以高生理濃度雌激素處理或用法洛德抑制胃癌細胞的雌激素受器能有效擾亂幽門螺旋桿菌感染所導致的各種不正常胃癌現象。我們的研究成果或許能為人類胃癌發生與進展調控機制帶來一線曙光。 | zh_TW |
| dc.description.abstract | This study is to elucidate the regulatory mechanism of estrogen receptors in Helicobacter pylori (H. pylori)-infected Gastric cancer. The correlation between H. pylori infection and gastric cancer was first analyzed using the cDNA microarray data from 8 gastric cancer patients. Among the differentially expressed H. pylori-related genes, 82 were found to be up-regulated two-fold. Ingenuity Pathway Analysis (IPA) analysis showed these genes to be highly related to four pathways with cancer progression, where estrogen receptor (ER) was the crucial hub in the network, and regulating 20 cancer related genes. A total of 14 ER-related genes were confirmed by q-RT-PCR to be up-regulated 1.5-fold in H. pylori-infected human AGS cells. Moreover, we utilized a human genome-wide high-affinity ERE database and built a new regulatory pathway for H. pylori-infected gastric cancer. Further experimental analysis included MTT assay, cell cycle analysis, oxidative stress resistance analysis, invasion assay, western blot, and q-RT-PCR. Our results show that either 1 nM estradiol or 10-5 M fulvestrant can reduce AGS viability, oxidative resistance, and metastasis that were increased by H. pylori infection. H. pylori enhanced the growth, resistance, and metastasis abilities of gastric cancer cells through ER-dependent pathway. With high physiological concentration of estradiol or shutting down ERs by fulvestrant, it can disturb abnormal gastric cancer conditions caused by H. pylori infection. Our results may shed light on the intricate regulatory mechanism in human gastric cancer formation and progression. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T06:46:47Z (GMT). No. of bitstreams: 1 ntu-100-R96b43004-1.pdf: 8188427 bytes, checksum: ce3d116a7edbfdb56aac2c0e462cfa0a (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | 口試委員審定書…………………………………..………………………………….I
誌 謝……………………..……………………………….…………….…………...….…....II 中文摘要 ..................................................................................................................... IV Abstract ....................................................................................................................... V Figure Contents…………………………………………….………………………..………......XIII Table Contents…………………………..…………..…………………………….….……….....XVI I. Introduction .............................................................................................................. 1 1. Gastric Cancer ................................................................................................... 1 1-1. One of the Most Fatal Cancerous Diseases in Taiwan ........................... 1 1-2. Classification of Gastric Cancer ............................................................. 1 1-3. Pathophysiology of Gastric Cancer ........................................................ 2 1-3-1. Genetic Inheritance, Gender, and Age ........................................ 2 1-3-2. Bacterial Infection ....................................................................... 3 1-3-3. Gastritis May Lead to Gastric Cancer ......................................... 3 2. Gastric Ulcer and Duodenal Ulcer .................................................................... 4 2-1. Peptic Ulcer ............................................................................................ 4 2-2. Pathophysiology of Peptic Ulcers .......................................................... 4 2-2-1. Bacteria Infection ........................................................................ 4 2-2-2. Other Causes of Bacteria Infection ............................................. 5 2-3. Diagnosis and Treatment for Peptic Ulcers ............................................ 5 2-3-1. Urea Breath Test for Detecting H. pylori Infection .................... 5 2-3-2. Antibiotics Treatment for H. pylori Infection ............................. 6 3. Helicobacter pylori ............................................................................................ 7 3-1. History .................................................................................................... 7 3-2. The Morphology and Culture Conditions of H. pylori ........................... 8 3-3. The Mechanisms of H. pylori Infection ................................................. 9 3-3-1. The “Leaking Roof” Concept ..................................................... 9 3-3-2. The Virulence Factors of H. pylori ............................................. 9 3-3-3. The Type IV Secretion Systems of H. pylori ............................ 10 3-4. The Virulence Factors of H. pylori ....................................................... 11 3-4-1. Adhesion Lipoprotein ............................................................... 11 3-4-2. Vacuolatingcytotoxin (VacA) .................................................... 12 3-4-3. Cytotoxin Associated Gene A (CagA) ...................................... 13 3-4-4. Urease ....................................................................................... 14 3-5. The Relationship between H. pylori and Gastric Cancer ..................... 15 3-6. The Effects of H. pylori on Proliferation and Apoptosis ...................... 16 3-6-1. H. pylori Can Increase Cancer Cell Viability ........................... 16 3-6-2. H. pylori Can Increase Antiapoptosis Response ....................... 17 3-7. Gastric Cancer Invasion and H. pylori Infection ................................. 17 3-8. H. pylori Treatments Nowadays ........................................................... 18 4. Hormone .......................................................................................................... 19 4-1. Overview .............................................................................................. 19 4-2. Steroid Hormones ................................................................................. 20 4-3. The Role of Estradiol in the Human Body ........................................... 20 4-4. Estrogen Receptors and Estrogen-Responsive Elements ..................... 21 4-4-1. Estrogen Receptors α and β ...................................................... 21 4-4-2. Estrogen-Responsive Elements ................................................. 22 5. Relationship between Estrogen, Gastric Cancer, and H. pylori ...................... 24 5-1. Estrogen and Gastric Cancer ................................................................ 24 5-2. Estrogen Receptors and Gastric Cancer ............................................... 25 5-3. Estrogen and H. pylori Infection .......................................................... 27 6. Research Purpose ............................................................................................. 28 II. Materials and Methods ........................................................................................ 30 1. The Construction of cDNA Microarray........................................................... 30 2. Using GeneSpring to Normalize Genes .......................................................... 31 3. Investigating GeneSpring Results with SAM .................................................. 31 4. Finding Over-Two-Fold Genes in H. pylori-infected Patients ........................ 32 5. Building Possible H. pylori-infected Networks by IPA .................................. 33 6. Estrogen Receptors and GAPDH Expression in Microarray ........................... 34 7. AGS Subculture and Freezing / Defreezing .................................................... 34 7-1. AGS Subculture .................................................................................... 34 7-2. Freezing of AGS ................................................................................... 35 7-3. Defreezing of AGS ............................................................................... 36 8. Helicobacter pylori Culture and Freezing / Defreezing .................................. 36 8-1. Helicobacter pylori Culture ................................................................. 36 8-2. Freezing and Defreezing of H. pylori................................................... 37 9. Verification of Possible H. pylori-infected Gastric Cancer Networks by Quantitative Polymerase Chain Reaction (q-RT-PCR) ................................... 37 9-1. q-RT-PCR Experiment ......................................................................... 37 9-2. Seeding of AGS .................................................................................... 38 9-3. Starvation of AGS ................................................................................ 39 9-4. H. pylori-infected AGS at Different Time Points (MOI) ..................... 39 9-5. Total RNA Extraction of AGS .............................................................. 41 9-5-1. RNA Extraction with TRIzol Reagent ...................................... 41 9-5-2. Extracting Total RNA from AGS .............................................. 41 9-6. Total RNA Electrophoresis of AGS...................................................... 43 9-7. Reverse Transcription (RT) of AGS ..................................................... 43 9-8. q-RT-PCR and Gene Analysis of H. pylori-infected AGS Cells .......... 44 9-8-1. Primers Designed and Synthesis ............................................... 44 9-8-2. The Process of q-RT-PCR……………………….………………...….44 10. Analyzing AGS Viability Influenced by H. pylori and Estradiol.................. 45 10-1. Phenol Red Free Medium and Charcoal Stripped FBS ...................... 45 10-2. β-Estradiol .......................................................................................... 45 10-3. Using MTT Assay to Measure AGS Viability .................................... 46 11. Analyzing AGS Cell Cycle by Flow Cytometry and PI Staining ................. 46 12. Analyzing AGS Oxidative Stress Resistance Influenced by H. pylori and Estradiol by Flow Cytometry and PI Staining ............................................... 47 13. Analyzing AGS Invasion Influenced by H. pylori and Estradiol Using in vitro Invasion Assay ............................................................................................... 48 14. Validating H. pylori-infected ER Network by q-RT-PCR ............................ 49 15. Fulvestrant Experiments ................................................................................ 50 15-1. Using MTT Assay to Analyze AGS Viability Influenced by Fulvestrant ..................................................................................................................... 50 15-2. The Fulvestrant Concentration Gradient Test by Western Blot .......... 51 15-2-1. Fulvestrant Treatment and AGS Total Protein Extraction ...... 51 15-2-2. SDS PAGE .............................................................................. 51 15-2-3. Protein Transfer and Blocking Process ................................... 52 15-2-4. Primary and Secondary Antibody Hybridization .................... 53 15-2-5. Protein Image Analysis ........................................................... 54 15-3. Using Western Blot to Analyze AGS ER α and β Influenced by H. pylori and Fulvestrant ........................................................................ 54 15-4. Using q-RT-PCR to Validate the H. pylori-infected Network Related Genes Influenced by Fulvestrant ....................................................... 55 III. Results .................................................................................................................. 56 1. The Normalization Processes of cDNA Microarray........................................ 56 1-1.The Normalization Results of 8 cDNA Microarray Data ...................... 56 1-2. Outliers Exclusion after Normalization………………………………..…....56 2. GeneSpring Results with SAM Analysis ........................................................ 57 2-1. Using FDR Value at 0.05 % ................................................................. 57 2-2. Using FDR Value at 32.06 % ............................................................... 57 3. Finding H. pylori-infection Genes with Over Two-Fold Change ................... 58 4. Constructing a Possible H. pylori-infected Network with the 82 Significant Genes by IPA ................................................................................................... 58 4-1. Estradiol was a Central Hub in Network 1 ........................................... 58 4-2. Merging Networks 1, 2, 3 and 4 ........................................................... 59 5. Estrogen Receptors and GAPDH Expression in Microarray ........................... 60 5-1. Estrogen Receptors (ERs) .................................................................... 60 5-2. GAPDH ................................................................................................ 60 6. Validating Genes in the New Network by q-RT-PCR .................................... 61 6-1. 14 Array Genes were Up-regulated ...................................................... 61 6-2. Both ER α and β Genes were Up-regulated ......................................... 62 7. Constructing an H. pylori-infected Network by ERE Database Mining ......... 62 8. AGS Viability Influenced by H. pylori and Estradiol ..................................... 63 9. AGS Cell Cycle Influenced by H. pylori and Estradiol .................................. 64 10. AGS Oxidative Stress Resistance Influenced by H. pylori and Estradiol ..... 64 10-1. AGS Cell Morphology ....................................................................... 64 10-2. PI Staining Results ............................................................................. 65 11. AGS Invasion Influenced by H. pylori and Estradiol .................................... 65 12. Genes in H. pylori-infected ERs Network Influenced by Estradiol .............. 66 13. AGS Viability Influenced by Fulvestrant ...................................................... 66 14. Fulvestrant Inhibition to ERs at Different Dosages....................................... 67 15. AGS ER α and β Protein Influenced by H. pylori and Fulvestrant ............... 67 16. Genes in H. pylori-infected ERs Network Influenced by Fulvestrant ........... 68 IV. Discussion ............................................................................................................. 69 1. New Treatments for H. pylori Infection .......................................................... 69 2. The FDR Value of SAM Filtering Result ........................................................ 70 3. An H. pylori-infected Gastric Cancer Network ............................................... 71 3-1. Metallothionein 1X, 1F, and 1G (MT1X, MT1F, and MT1G) ............. 72 3-2. Left-Right Determination Factor 2 (LEFTY2)..................................... 73 3-3. Immunoglobulin J Polypeptide (IGJ) ................................................... 73 3-4. Cyclin D2 (CCND2) ............................................................................ 74 3-5. Insulin-Like Growth Factor Binding Protein 5 (IGFBP5) ................... 75 3-6. Interferon Regulatory Factor 4 (IRF4) ................................................. 76 3-7. Metallophosphoesterase Domain Containing 2 (MPPED2) ................ 77 3-8. Quiescin Q6 Sulfhydryl Oxidase 1 (QSOX1) ...................................... 77 3-9. Wolfram Syndrome 1 (wolframin, WFS1) ........................................... 78 3-10. ATPase Na+/K+ Transporting Beta 1 Polypeptide (ATP1B1) ............. 79 3-11. Anterior Gradient Homolog 2 (AGR2) .............................................. 80 3-12. Kallikrein-Related Peptidase 11 (KLK11) ......................................... 81 4. The Constructed Network was Highly Related to Gastric Cancer .................. 82 5. AGS Viability, Cell Cycle, and Invasion Influenced by H. pylori and Estradiol…. ...................................................................................................... 83 6. AGS Oxidative Stress Resistance Influenced by H. pylori and Estradiol ....... 84 7. Estradiol Protects Human Against H. pylori-infected Gastric Cancer ............ 86 8. H. pylori Infection was Estrogen Receptor Dependent ................................... 87 9. The Hypothesis for H. pylori Infection and Protective Role of Estradiol against H. pylori-infected Gastric Cancer .................................................................... 88 V. Future Works ......................................................................................................... 90 1. Finding Estradiol Analogues or Upstream ER-regulated Pathways ................ 90 2. Verifying Whether ERs Undergo Conformational Changes or are Activated by H. pylori ........................................................................................................... 91 3. Estradiol Treatment for H. pylori Infection ..................................................... 92 4. The Animal Model for Long-term H. pylori Infection and Estradiol Treatment………………………………………………………………..………………….93 VII. List of Figures and Tables ............................................................................... 117 VIII. Publications .................................................................................................... 172 Figure 1. The incidence of gastric and cardia gastric adenocarcinoma in Sweden between 1970 and 2005…………………………………….………….……….117 Figure 2. The inflammation in the stomach (gastritis)…………………………..…..…118 Figure 3. Carbon-14-urea breath Test………………...…………………………….....…119 Figure 4. Gastric acid is secreted by parietal cells of the stomach in response to stimulation…………………………...…………………...………...…...…….....120 Figure 5. Morphologies of H. pylori………………………..………..…………..…........121 Figure 6. H. pylori causes stomach ulcers………………………..……………....….......122 Figure 7. Models of the assembly process and the assembled structure of the T4SS machinery…………………….…………………………….…………………....123 Figure 8. Helicobacter pylori-induced signaling to the nucleus and the actin cytoskeleton…………………………………………………….…………….....124 Figure 9. H. pylori activates pathways that down-regulate apoptosis………....….......125 Figure 10. Steroid hormones response………………………..…………………….…...126 Figure 11. The structural formula of human 17-β estradiol…………...…………….....127 Figure 12. Distributions of estrogen receptor α and β (ER α and β) in different tissues………………………...……………..………..……………………...…127 Figure 13. Estradiol response………………………...……………………………....…...128 Figure 14. The structural formula of estradiol antagonist: fulvestrant…..……...….....129 Figure 15. Incidence of gastric cancer male-to-female (M/F) ratio………..…….…...129 Figure 16. Annual age-group-specific incidences of gastric cancer…………...……...130 Figure 17. Modes of action of estradiol, tamoxifen, and fulvestrant……...……...…..131 Figure 18. H. pylori signaling pathways………………………………..………….…....132 Figure 19. The experimental flowchart………………………..………………………...133 Figure 20. The normalization results of 8 gastric cancer patients’ tissue cDNA microarray data………………………………..………………………..…..…134 Figure 21. Eliminating genes intensities lower than 500...…………………..……...…135 Figure 22. SAM operating window……………………………………………..…..…...136 Figure 23. SAM analyzed results with different FDR value…………………..…...….137 Figure 24. The distance tree clustering result of 7 genes………………………...........138 Figure 25. The clustering results of 8 cDNA microarray data from H. pylori-infected gastric cancer patients………...…………………………..………………......139 Figure 26. The IPA networks of 82 genes………………………..………..………….....140 Figure 27. The IPA Network1…………………...……………………………..……..…..141 Figure 28. IPA Networks 2, 3, and 4……………………………………..………............142 Figure 29. Functional analysis of IPA Network1 ~ 4…………..…….……………...…143 Figure 30. The merging result of IPA Network 1 ~ 4……………………..….…..…….144 Figure 31. The fold changes of estrogen receptors and GAPDH in microarray…......145 Figure 32. The example of total RNA electrophoresis………………..…………......…146 Figure 33. Results of 16 genes time course q-RT-PCR experiments……...…......147-148 Figure 34. q-RT-PCR time-course analysis of H. pylori infection…..…………..….....149 Figure 35. The ERs related network of H. pylori infection……………..………..……150 Figure 36. The novel network was highly cancer related………………………....…...151 Figure 37. The cancerous functions of the novel H. pylori infection network……....151 Figure 38. AGS viability influenced by H. pylori and estradiol…...…….…………....152 Figure 39. AGS cell cycle influenced by H. pylori and estradiol…...…………...…....153 Figure 40. AGS oxidative stress resistance influenced by H. pylori and estradiol……………………………………………………………...…………154 Figure 41. AGS oxidative stress resistance influenced by H. pylori and estradiol (2)………......…….……………………...………………………………...……155 Figure 42. AGS invasive ability influenced by H. pylori and estradiol………....…....156 Figure 43. Genes in the H. pylori-infected network influenced by estradiol…………...………..………………………………………………......157 Figure 44. AGS viability influenced by fulvestrant…….………..……………..………158 Figure 45. The ERs inhibition ability of different fulvestrant concentration…..….....159 Figure 46. AGS ERs protein expression influenced by H. pylori and fulvestrant……………...………………………..…………………………..…160 Figure 47. Genes in the H. pylori-infected ERs network influenced by fulvestrant………...…………………………..……………………………......161 Figure 48. The novel hypothesis for H. pylori infection and the protective role of estradiol against H. pylori-infected gastric cancer……..………..……..…..162 Table 1. 118 up-regulated genes filtered by SAM……….…………..……………..........163 Table 2. 82 two-fold up-regulated genes filtered by GeneSpring……...……..............164 Table 3. Interactions between estradiol and other molecules in Network 1 merged with Networks 2, 3, and 4…………….………………………..…………….…….165 Table 4. The cellular functions of 20 genes in Network 1 (merged)…………..….....166 Table 5. Primer sequences and information of 22 genes in merged Network 1.……………………...……………………………………………….167-168 Table 6. ERE information of genes in the novel H. pylori-infected gastric cancer network……………………….…………..………..………………………………..…169 Table 7. cDNA microarray data of gastric cancer tissues and H. pylori……..…..….170 Table 8. The maximum fold change and time points of 20 genes in H. pylori infected network…………..………...………………...………………..……………171 | |
| dc.language.iso | zh-TW | |
| dc.subject | 胃癌 | zh_TW |
| dc.subject | 幽門螺旋桿菌 | zh_TW |
| dc.subject | 雌激素 | zh_TW |
| dc.subject | 雌激素受器 | zh_TW |
| dc.subject | 互補去氧核醣核酸微陣列晶片 | zh_TW |
| dc.subject | 調控機制 | zh_TW |
| dc.subject | cDNA microarray | en |
| dc.subject | estrogen receptors | en |
| dc.subject | Gastric cancer | en |
| dc.subject | regulatory mechanism | en |
| dc.subject | estradiol | en |
| dc.subject | Helicobacter pylori | en |
| dc.title | 探討胃幽門螺旋桿菌感染後所誘導的雌激素受器調控路徑 | zh_TW |
| dc.title | Elucidating Regulatory Pathway of Estrogen Receptors in Helicobacter pylori-infected Gastric Cancer | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 黃宣誠(Hsuan-Cheng Huang),陳炯年(Chiung-Nien Chen),應靜雯(Ching-Wen Ying),周涵怡(Han-Yi Elizabeth Chou) | |
| dc.subject.keyword | 胃癌,幽門螺旋桿菌,雌激素,雌激素受器,互補去氧核醣核酸微陣列晶片,調控機制, | zh_TW |
| dc.subject.keyword | Gastric cancer,Helicobacter pylori,estradiol,estrogen receptors,cDNA microarray,regulatory mechanism, | en |
| dc.relation.page | 178 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2011-06-16 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 分子與細胞生物學研究所 | zh_TW |
| 顯示於系所單位： | 分子與細胞生物學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-100-1.pdf 未授權公開取用 | 8 MB | Adobe PDF |
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