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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 郭明良 | |
| dc.contributor.author | Tsang-Chih Kuo | en |
| dc.contributor.author | 郭倉志 | zh_TW |
| dc.date.accessioned | 2021-06-07T17:49:50Z | - |
| dc.date.copyright | 2013-03-04 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-01-28 | |
| dc.identifier.citation | 1. Fidler, I.J. 2003. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer 3:453-458.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/15674 | - |
| dc.description.abstract | 癌症轉移是主要造成癌症病人死亡的主因。找出抑制腫瘤轉移之分子並了解其分子機制，可做為病理診斷上的新方法且有益於發展有效的抗癌藥物。血管生成相似素1 (ANGPTL1)為血管生成相似素(ANGPTL)的家庭成員之ㄧ，已經被報導可以抑制內皮細胞增生、遷移、管腔形成和粘附。越來越多證據指出ANGPTL的家庭成員除了可針對內皮細胞去調控血管新生之外，也被報導可以影響腫瘤細胞。然而，ANGPTL1對於腫瘤細胞本身的影響尚不清楚。在我們的研究中發現腫瘤組織中ANGPTL1表現量的多寡和癌細胞浸襲、淋巴轉移及癌症病患的預後有高度相關性。在細胞模式和動物實驗中發現ANGPTL1透過降低人蝸牛同源物2 (Slug) 的表現，顯著的抑制癌細胞的遷移、浸襲和轉移能力。進一步探討ANGPTL1如何調控Slug則發現，ANGPTL1抑制Slug的蛋白表現，不是經由改變Slug的mRNA表現及Slug蛋白的半衰期。ANGPTL1是透過增加微小核苷酸-630 (miR-630)去抑制Slug的表現。我們也證明了ANGPTL1藉由和整合素α1β1 (integrin α1β1)的結合並抑制其下游FAK/ERK訊息傳遞途徑去調控轉錄因子Sp-1所主導的miR-630−Slug的表現，進而干擾癌細胞的移動和轉移。因此，ANGPTL1可做為未來治療癌症轉移之一有潛力的蛋白藥物。 | zh_TW |
| dc.description.abstract | Metastasis is the most important contributor to mortality in cancer patients. Identification of novel tumor metastasis suppressors and elucidation of the molecular mechanisms can provide new insights into the pathogenesis and development of effective anticancer drugs. Angiopoietin-like protein 1 (ANGPTL1), a member of the angiopoietin-like protein family, has been reported as an anti-angiogenic molecule that inhibits proliferation, migration, tube formation, and adhesion of endothelial cells. Growing evidence suggests that certain ANGPTL proteins not only target endothelial cells but also affect tumor cell behaviors. Whether ANGPTL1 can influence the malignant properties of cancer cells remains unclear. In this study, we show that ANGPTL1 expression inversely correlates with invasion, lymph node metastasis, and poor clinical outcomes in cancer patients. We also found that ANGPTL1 significantly suppresses the migratory, invasive, and metastatic capabilities of cancer cells through downregulation of the zinc-finger protein Slug. Further evidence has shown that ANGPTL1-mediated Slug protein downregulation is not attributed to decreased mRNA levels or facilitated protein degradation. Meanwhile, we have determined that ANGPTL1-mediated suppression of the Slug protein is due to the induction of miR-630 transcripts in the Sp-1–dependent ERK pathway. Furthermore, we show that ANGPTL1 interacts with integrin α1β1 and represses its downstream signaling, FAK/ERK to reduce cancer cell motility and invasiveness. These findings indicate that ANGPTL1 inhibits cancer cell motility and metastasis by inducing the mesenchymal-epithelial transition via the integrin α1β1−FAK−ERK−Sp-1−miR-630−Slug signal cascade. Therefore, ANGPTL1 may act as a potential powerful therapeutic protein drug for cancer treatment. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-07T17:49:50Z (GMT). No. of bitstreams: 1 ntu-102-F95447013-1.pdf: 5000585 bytes, checksum: 2df2ab1c2ebf3a86bfb3d4b1ceb47344 (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | 摘要.....................1
Abstract.................2 List of Figures..........4 List of Tables...........5 Chapter1. Introduction...6 1.1 Tumor metastasis.....7 1.2 Angiopoietins and angiopoietin-like proteins (ANGPTLs).9 1.3 Epithelial-to-mesenchymal transition (EMT) and Slug...12 1.4 MicroRNAs (miRNAs) and tumor metastasis...14 1.5 Motivation and purpose...16 Chapter2. Materials and Methods...17 Chapter3. Results...29 3.1 ANGPTL1 expression inversely correlates with poor prognosis of cancer patients...30 3.2 ANGPTL1 inhibits cancer cell migration, invasion, and metastasis...31 3.3 ANGPTL1 induces mesenchymal-epithelial transition by down-regulating Slug...32 3 4 ANGPTL1 represses Slug expression by inducing expression of miR-630...34 3.5 ANGPTL1 interacts with integrin α1β1 and represses the downstream signaling and Slug expression...36 3.6 ANGPTL1 induces miR-630 transcription through repression of the ERK/Sp-1 pathway...38 Chapter4. Discussion...40 Figures and figure legends...44 Tables...78 References...84 Appendix...92 | |
| dc.language.iso | en | |
| dc.subject | 轉移 | zh_TW |
| dc.subject | 浸襲 | zh_TW |
| dc.subject | 人蝸牛同源物2 | zh_TW |
| dc.subject | 間質到上皮轉化 | zh_TW |
| dc.subject | 血管生成相似素1 | zh_TW |
| dc.subject | metastasis | en |
| dc.subject | Slug | en |
| dc.subject | mesenchymal-epithelial transition | en |
| dc.subject | ANGPTL1 | en |
| dc.subject | invasion | en |
| dc.title | 探討血管生成相似素1於癌細胞浸襲及轉移過程中之角色 | zh_TW |
| dc.title | The Role of Angiopoietin-like 1 Protein (ANGPTL1) in Cancer Cell Invasion and Metastasis | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 王朝鐘,吳國瑞,洪文俊,蕭宏昇 | |
| dc.subject.keyword | 血管生成相似素1,間質到上皮轉化,人蝸牛同源物2,浸襲,轉移, | zh_TW |
| dc.subject.keyword | ANGPTL1,mesenchymal-epithelial transition,Slug,,invasion,metastasis, | en |
| dc.relation.page | 92 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2013-01-28 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 毒理學研究所 | zh_TW |
| 顯示於系所單位： | 毒理學研究所 | |
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