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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 郭明良 | |
| dc.contributor.author | I-Hsin Kuo | en |
| dc.contributor.author | 郭亦炘 | zh_TW |
| dc.date.accessioned | 2021-06-13T05:45:06Z | - |
| dc.date.available | 2006-08-03 | |
| dc.date.copyright | 2006-08-03 | |
| dc.date.issued | 2006 | |
| dc.date.submitted | 2006-07-14 | |
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(2002) Fibrillar collagen regulation of plasminogen activator inhibitor-1 is involved in altered smooth muscle cell migration. Arterioscler Thromb Vasc Biol 22, 1573-1578 56. Waltz, D. A., Natkin, L. R., Fujita, R. M., Wei, Y., and Chapman, H. A. (1997) Plasmin and plasminogen activator inhibitor type 1 promote cellular motility by regulating the interaction between the urokinase receptor and vitronectin. J Clin Invest 100, 58-67 | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/33725 | - |
| dc.description.abstract | Cyr61 (Cysteine-rich protein 61) 是CCN家族的成員之一, 先前本實驗室的研究指出Cyr61的表現與胃癌腫瘤的形成直接相關, 然而Cyr61在腫瘤浸襲所扮演的角色仍不甚明瞭。腫瘤的轉移與浸襲往往決定人類癌症的惡性程度，近幾年在研究上也逐漸被重視。本研究主要探討Cyr61與HIF-1α在胃癌細胞的相關性,並且研究HIF-1α是否在Cyr61所誘發的腫瘤侵襲能力上扮演重要的角色。
我們發現在不同的胃癌細胞株, HIF-1α蛋白表現量與Cyr61呈正相關, 並利用短暫轉殖Cyr61質體以及外加Cyr61重組蛋白,都可誘發HIF-1α蛋白表現量。在機制探討方面, 發現Cyr61透過蛋白新合成的方式增加HIF-1α蛋白表現, 且透過PI3K/AKT/mTOR 以及ERK1/2訊息傳導路徑調控HIF-1α。我們更進一步研究HIF-1α在Cyr61高表現的細胞株中是否扮演調控癌細胞浸襲能力之角色, 實驗結果顯示, 短暫轉殖DN-HIF-1α質體阻斷HIF-1α的功能性, 可以抑制Cyr61所促進之侵襲能力。 接下來我們篩選了HIF-1α下游調控細胞移動與侵襲能力的相關基因, 發現外加處理Cyr61重組蛋白可以明顯增加PAI-1基因的表現, 並利用ChIP 檢測方法,證明HIF-1α直接調控PAI-1。最後探討PAI-1是否參與了Cyr61所調控之胃癌細胞浸襲能力, 實驗結果顯示, 當處理抗PAI-1寡核苷酸以及中和抗體抑制PAI-1的活性, 可以降低Cyr61調控之癌細胞浸襲能力。綜合以上實驗結果, Cyr61可以透過 HIF-1α調控之PAI-1基因促進胃癌細胞的浸襲能力。 | zh_TW |
| dc.description.abstract | Cyr61, one of the members of CCN family, has been implicated in the progression of human gastric adenocarcinoma. However, the mechanism underlying Cyr61’s effect on tumor progression remains widely unknown. Tumor invasion and metastasis are the critical steps in determining the aggressive phenotype of human cancers, and recently received more attention. Here, we study the interaction between Cyr61 and HIF-1α, which are involved in tumor progression, in human gastric cancer cells and cell invasion ability.
We found that HIF-1α protein expression was significantly elevated in cells overexpressing Cyr61. Cyr61-mediated HIF-1α up-regulation was through de novo protein synthesis. At the mechanistic level, Cyr61 could activate the PI3K/AKT/mTOR and ERK1/2 signaling pathways and this activation was essential for HIF-1α induction. Blockage of HIF-1α activity in Cyr61-expressing cells by transfecting with a dominant negative (DN)- HIF-1α inhibited tumor invasion ability. In addition, several HIF-1α-regulated invasiveness genes were examined, and we found that only PAI-1 showed a significant increase in mRNA and protein in cells overexpressing Cyr61. Treatment with inhibiting PAI-1-specific oligonucleotides antisense or function-neutralizing antibodies abolished the invasion ability of the Cyr61-overexpressing cells. At the same time, transfection of DN-HIF-1α to block HIF-1α activity also effectively reduced the elevated PAI-1 level. In conclusion, our data suggested a detailed mechanism describing the underlying role of Cyr61 in gastric cancer cell invasive ability via a HIF-1α-dependent up-regulation of PAI-1. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T05:45:06Z (GMT). No. of bitstreams: 1 ntu-95-R93447001-1.pdf: 1570247 bytes, checksum: 50d2f0aad0d4368a92969e0ec5076756 (MD5) Previous issue date: 2006 | en |
| dc.description.tableofcontents | Abstract 4
中文摘要 5 INTRODUCTION 6 EXPERIMENTAL PROCEDURES 9 Regents and Antibodies 9 Cell Cultures 9 Stable and Transient Transfections 10 RNA Isolation and Reverse Transcriptase-PCR 10 Western Blot Analysis 11 HIF-1α reporter Activity Assay 11 Immunofluorescence Staining 12 Boyden chamber assay 12 PAI-1 Antisense Oligonucleotides 13 Chromatin Immunoprecipitation Assay 13 RESULTS 14 Cyr61 stimulates HIF-1α accumulation and activation in human gastric carcinoma cells. 14 Cyr61 induces HIF-1α expression through de novo protein synthesis. 16 Cyr61 stimulates HIF-1α accumulation through a PI3K and MAPK-dependent pathway. 17 HIF-1α expression is strictly correlated with Cyr61-induced invasion in different gastric cancer cell lines. 19 PAI-1 acts as a downstream effector of Cyr61. 19 Cyr61 regulates PAI-1 expression via HIF-1α pathway. 21 DISCUSSION 22 REFERENCE 27 FIGURES AND FIGURE LEGENDS 33 FIGURE 1. Cyr61 Stimulates HIF-1α Accumulation and Activation in Human Gastric Carcinoma Cells. 37 FIGURE 2. Cyr61 Induces HIF-1α Expression Through de novo Protein Synthesis. 40 FIGURE 3. Cyr61 stimulateds HIF-1α accumulation through a PI3K and MAPK-dependent pathway. 42 FIGURE 4. HIF-1α expression is strictly correlated with Cyr61-induced invasion in human gastric cancer cells. 45 FIGURE 5. PAI-1 is involved in Cyr61-mediated gastric cancer cell invasion. 49 FIGURE 6. Expression of Cyr61 increases the HIF-1α-dependent invasion protein PAI-1 52 FIGURE 7. Proposed invasive molecular mechanisms of HIF-1α-mediated PAI-1 expression in Cyr61-overexpressing cells. 53 | |
| dc.language.iso | en | |
| dc.title | HIF-1α 於Cyr61促進胃癌浸襲之研究 | zh_TW |
| dc.title | The role of HIF-1α in Cyr61-enhanced gastric cancer invasion | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 94-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 王朝鍾,翁一鳴,林明燦,莊雙恩,鄭安理 | |
| dc.subject.keyword | 胃癌,浸襲能力, | zh_TW |
| dc.subject.keyword | Cyr61,HIF-1,Gastric cancer,Invasion, | en |
| dc.relation.page | 53 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2006-07-14 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 毒理學研究所 | zh_TW |
| Appears in Collections: | 毒理學研究所 | |
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