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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 潘思樺(Szu-Hua Pan) | |
dc.contributor.author | Yuan-Ling Hsu | en |
dc.contributor.author | 許元玲 | zh_TW |
dc.date.accessioned | 2021-07-10T21:43:59Z | - |
dc.date.available | 2021-07-10T21:43:59Z | - |
dc.date.copyright | 2020-09-10 | |
dc.date.issued | 2020 | |
dc.date.submitted | 2020-07-23 | |
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Wang, W.L., T.M. Hong, Y.L. Chang, C.T. Wu, S.H. Pan, and P.C. Yang, Phosphorylation of LCRMP-1 by GSK3beta promotes filopoda formation, migration and invasion abilities in lung cancer cells. PLoS One, 2012. 7(2): p. e31689. 119. Chiang, H.C., The role of long form CRMP-1 in mesenchymal-endothelial transition: focus on lung cancer. Graduate Institute of Medical Genomics and Proteomics Collage of Medicine National Taiwan University Master Thesis, 2017. 120. Brot, S., V. Rogemond, V. Perrot, N. Chounlamountri, C. Auger, J. Honnorat, and M. Moradi-Ameli, CRMP5 interacts with tubulin to inhibit neurite outgrowth, thereby modulating the function of CRMP2. J Neurosci, 2010. 30(32): p. 10639-54. 121. Chand, H.S., S.A. Ness, and W. Kisiel, Identification of a novel human tissue factor splice variant that is upregulated in tumor cells. Int J Cancer, 2006. 118(7): p. 1713-20. 122. Zhou, R.F., Y. Liu, Y.X. Wang, W. Mo, and M. 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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77031 | - |
dc.description.abstract | 癌症是一複雜的過程,其包含了腫瘤細胞的增生、腫瘤新生血管的形成以及腫瘤細胞的轉移等步驟。腫瘤可藉由周邊血管的形成而獲得血中的氧氣及養分,也因此促使了腫瘤的生長以及轉移的發生。由於新生血管對於癌症進程的重要性,科學家們對於腫瘤新生血管的形成進行了許多研究。至今,主要被探討的腫瘤新生血管形成作用可區分為兩類,其一為血管新生,其二為血管擬態。血管新生意即所新生的血管源自於內皮細胞;血管擬態則指癌細胞自身可排列為類血管構造,此兩種血管生成作用皆提供了癌細胞進行轉移的通路。早期,實驗室團隊利用cDNA微陣列晶片對肺腺癌進行研究,發現ID4和LCRMP-1的表現量與癌細胞的侵襲能力有所關聯。然而,兩者在肺癌惡化的進程中所扮演的功能性角色以及所調控的分子機制仍然存在著許多未知值得我們詳細探討。 我們在早期研究中發現ID4是一個會抑制癌細胞移動及侵襲等轉移能力的基因,然而對於其分子調控機制及其在臨床病人上的真實表現情況未進行詳細的探討。在本研究計畫中,為了進一步釐清ID4之於癌轉移分子調控機制的影響,我們再次利用cDNA晶片進行分析,確認了ID4最主要調控的訊息路徑包含了上皮細胞間質轉換作用調控路徑,並發現ID4可透過與SLUG蛋白質結合而促進E-cadherin的表現,達成間質細胞上皮轉換作用而抑制癌轉移。除此之外,在利用臨床資料庫進行分析後,證實ID4表現量與病人存活率呈現負相關,此論述支持ID4可作為一判定肺腺癌病人病程的癌症指標。 另一方面,本實驗團隊在2009年時已證實LCRMP-1扮演著提升侵襲能力的角色,其透過與肌動蛋白核化骨架蛋白WAVE-1的結合增加細胞絲狀偽足的形成,進而促使肺腺癌病人病程惡化。在本研究中,我們發現 LCRMP-1除了刺激癌細胞的侵襲轉移能力外,也與肺癌組織內的血管密度具有正相關的關聯性。進一步地,我們在本研究中揭示了腫瘤細胞中LCRMP-1可作為轉錄作用的協同活化者調控SERPINE1等血管新生因子的分泌而刺激血管新生作用,誘使內皮細胞形成新的微血管;除此之外,表現LCRMP-1的腫瘤細胞也可透過執行內皮細胞轉換作用形成類血管。 綜合上述,本研究的發現對於釐清肺腺癌中與癌症惡化相關之基因所扮演的角色有所助力,並使其能作為未來開發新型抗癌藥物的標的物或是監測癌症病程的診斷指標。 | zh_TW |
dc.description.abstract | Cancer malignancy is a complex process including tumor neo-vascularization and metastasis. Tumors can rapidly grow and even occur metastasis with neo-vessels to supply the nutrients and oxygens. Till now, two types of blood vessel formation are explored, one is angiogenesis and the other is called vasculogenic mimicry. The former indicates that neo-blood vessels are indirectly formed by endothelial cells; and the latter showed that cancer cells, other than endothelial cells, can directly form blood vessels by itself. Both phenotypes of micro-vessels in tumor arrange the roads that cancer cells can metastasize to distant organs. Previously, our research team discovered that the expressions of inhibitor of DNA binding protein 4 (ID4) and long form collapsin response mediator protein 1 (LCRMP-1) were related to cell invasiveness in lung adenocarcinoma (LADC) cells by cDNA microarray screening. However, the functional roles and their mechanisms of regulation in lung cancer malignancy including vascularization and metastasis remain unclear. Recently, we have displayed ID4 as a new metastasis-related gene which attenuated migration and invasion. However, we did not clarify the regulatory mechanism and the effects of clinical outcome in LADC patients at that time. In order to recognize the regulatory of mechanism in detail, we used cDNA microarray analysis, and presented epithelial-mesenchymal transition (EMT) pathway was the major pathway which ID4 regulated. Moreover, we found that ID4 can promote E-cadherin expression through the binding of SLUG, cause the occurrence of mesenchymal-epithelial transition (MET), and inhibit cancer metastasis. Additionally, we used the clinical database to display that the negative correlation between ID4-expressing level and the survival in LADC patients. The facts supported that ID4 might play as a diagnostic marker in LADC. On the other hand, our laboratory has demonstrated LCRMP-1 is an invasive enhancer, which promoted lung cancer malignancy by increasing the formation of filopodia through binding to the actin nucleation scaffold protein, WAVE-1 in 2009. In this study, we found LCRMP-1 not only promoted cancer metastasis but also had a positive correlation with blood vessel densities in lung tumor tissues. According to the finding, we hypothesized LCRMP-1 may play as an enhancer in tumor vascularization. Moreover, we illustrated that LCRMP-1 played as a transcriptional co-activator in tumor cells. The expression of LCRMP-1 could manipulate the secretion of angiogenic factors such as SERPINE1 to induce endothelial cells forming new micro-vessels, or form mimic neo-blood vessels via endothelial-like cell transformation. In the conclusion, we hope our findings can help us more understanding the role of malignant-related genes in LADC, and to develop the new anticancer therapies or diagnosis markers in the near future. | en |
dc.description.provenance | Made available in DSpace on 2021-07-10T21:43:59Z (GMT). No. of bitstreams: 1 U0001-2107202012540500.pdf: 10397666 bytes, checksum: d47109c1c1fecd824c494e54583c3fbe (MD5) Previous issue date: 2020 | en |
dc.description.tableofcontents | 口試委員會審定書 i 誌謝 ii 中文摘要 iii Abstract v Chapter One: General Introduction 1 1.1 Cancer 2 1.1.1 Characteristics of malignant cancer 2 1.1.2 Tumor growth and vascularization 2 1.1.3 Cancer metastasis 3 1.1.4 Lung adenocarcinoma 4 1.2 The regulators in cancer malignancy 5 1.2.1 Inhibitor of DNA binding proteins (IDs) 5 1.2.1.1 The functional role of IDs 5 1.2.1.2 IDs and cancer 5 1.2.2 Collapsin response mediator proteins (CRMPs) 6 1.2.2.1 The functional role of CRMPs 7 1.2.2.2 CRMPs and cancer 7 1.3 Specific aims of this thesis 8 Chapter Two: ID4 Suppresses Cancer Metastasis through the Regulation of Epithelial Mesenchymal Transition 10 2.1 Abstract 11 2.2 Introduction 12 2.2.1 Cancer metastasis 12 2.2.1.1 Epithelial-mesenchymal transition (EMT) 12 2.2.2 Inhibitor of DNA binding protein 4 (ID4) 13 2.2.3 Hypothesis and specific aim 14 2.3 Materials and methods 15 2.3.1 Cell lines and culture condition 15 2.3.2 Reverse transcriptase polymerase chain reaction (RT-PCR) and microarray analysis 15 2.3.3 Plasmid constructs and stable cell selection 16 2.3.4 Short hairpin RNA (shRNA) and Lentiviral infection 16 2.3.5 Immunoprecipitation and immunoblotting 17 2.3.6 Cell proliferation and apoptosis 18 2.3.7 Modified Boyden chamber invasion assay 18 2.3.8 Luciferase reporter assay 19 2.3.9 Chromatin immunoprecipitation assay (ChIP) 19 2.3.10 Tail vein assay 20 2.3.11 IHC analysis of tumor samples from the lungs of mice 21 2.3.12 TUNEL assay 21 2.3.13 Statistical analysis 22 2.4 Results 23 2.4.1 ID4 expression inversely correlates with lung cancer cell invasiveness 23 2.4.2 Expression of ID4 could interfere with malignancy in vitro and in vivo 24 2.4.3 ID4 affects cancer cell malignancy through the regulation of epithelial-mesenchymal transition 26 2.4.4 ID4 promotes E-CAD expression through the binding of SLUG 28 2.4.5 Low-level ID4 expressions are associated with a poor clinical outcome form LADC patient 30 2.5 Summary 33 2.6 Discussion 34 Chapter Three: LCRMP-1 Induces Tumor Neo-vascularization through Regulating Angiogenesis and Vasculogenic Mimicry 58 3.1 Abstract 59 3.2 Introduction 62 3.2.1 Tumor vascularization 62 3.2.1.1 Angiogenesis 62 3.2.1.2 Vasculogenic mimicry 65 3.2.2 Long form collapsin response mediator protein 1 (LCRMP-1) 66 3.2.2.1 CRMP-1 and LCRMP-1 66 3.2.2.2 LCRMP-1 and cancer metastasis 67 3.2.3 Hypothesis and specific aims 67 3.3 Materials and methods 69 3.3.1 Cell lines and culture conditions 69 3.3.2 Patients and tumor specimens 70 3.3.3 Plasmids for transfection 71 3.3.4 The establishment of LCRMP-1 expressing stable cell lines 72 3.3.5 Antibodies 72 3.3.6 Lentivirus production and transduction 73 3.3.7 Colony formation assay 73 3.3.8 Xenograft tumor formation assay in vivo 74 3.3.9 Immunohistochemical analysis of LCRMP-1 and micro-vessel density in tumor samples from experimental tumor growth in vivo. or patients with NSCLC 74 3.3.10 Tube formation assay 75 3.3.11 Endothelial cell migration assay 76 3.3.12 Plaque angiogenesis assay in vivo 76 3.3.13 RNA extraction for microarray, reverse transcriptase PCR (RT-PCR), quantitative real time PCR (Q-PCR) 77 3.3.14 Human angiogenesis antibody array 77 3.3.15 Isolation protein from cellular fractions 78 3.3.16 Immunofluorescence staining for observation of protein localization 79 3.3.17 Immunoprecipitation and immunoblotting 79 3.3.18 Luciferase assay 81 3.3.19 Chromatin immunoprecipitation 81 3.3.20 Electrophoretic mobility shift assay 81 3.3.21 In vitro 3D cancer-endothelial cells co-culture system 82 3.3.22 PAS staining and RNAscope assay in tumor samples from experimental tumor growth in vivo 82 3.3.23 Statistics 83 3.4 Results 85 3.4.1 LCRMP-1 promotes tumor growth 85 3.4.2 The expression of LCRMP-1 protein positively correlates with angiogenesis 86 3.4.3 The conditioned medium from LCRMP-1 expression cells promotes angiogenesis 88 3.4.4 LCRMP-1 is not a secretory protein 89 3.4.5 SERPINE1 is the potent target that LCRMP-1 controlling in angiogenesis 90 3.4.6 LCRMP-1 promotes the transcription of SERPINE1 and induces angiogenesis 91 3.4.7 LCRMP-1 may locate in nucleus and control angiogenesis 93 3.4.8 TP53 is the potent candidate that connects the interaction between LCRMP-1 and SERPINE1 promoter 94 3.4.9 LCRMP-1 interacts with TP53 to upregulate SERPINE1 promoter activity 95 3.4.10 Other transcriptional factors such as AP1 assist LCRMP-1 to manipulate transcription of SERPINE1 97 3.4.11 LCRMP-1 regulates the promoter activity of SERPINE1 with specific N-terminal region. 98 3.4.12 LCRMP-1 causes vasculogenic mimicry in vitro 99 3.4.13 LCRMP-1 manipulates vasculogenic mimicry through morphology transition 100 3.4.14 LCRMP-1 promotes vasculogenic mimicry via MEndoT which regulated by VM markers in transcriptional level 101 3.5 Summary 103 3.6 Discussion 104 Chapter Four: Conclusion and Future Works 152 Abbreviation 162 Reference 166 Appendix 185 | |
dc.language.iso | en | |
dc.title | 探討LCRMP-1及ID4蛋白質在惡性肺癌中之調控機制 | zh_TW |
dc.title | Exploring the Role of LCRMP-1 and ID4 in Malignant Lung Cancer | en |
dc.type | Thesis | |
dc.date.schoolyear | 108-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 洪澤民(Tse-Ming Hong),陳佑宗(You-Tzung Chen),陳金銓(Chin-Chuan Chen),蔡丰喬(Feng-Chiao Tsai) | |
dc.subject.keyword | 肺腺癌,血管新生,血管擬態,轉移,ID4,LCRMP-1, | zh_TW |
dc.subject.keyword | lung adenocarcinoma,angiogenesis,vasculogenic mimicry,metastasis,ID4,LCRMP-1, | en |
dc.relation.page | 187 | |
dc.identifier.doi | 10.6342/NTU202001685 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2020-07-24 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 基因體暨蛋白體醫學研究所 | zh_TW |
顯示於系所單位: | 基因體暨蛋白體醫學研究所 |
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