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系統識別號 U0026-2407201214564900
論文名稱(中文) Sp1在乳癌發展中所扮演的角色
論文名稱(英文) The role of Sp1 in breast cancer progression
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 100
學期 2
出版年 101
研究生(中文) 王毅昌
研究生(英文) Yi-Chang Wang
學號 s26991089
學位類別 碩士
語文別 中文
論文頁數 66頁
口試委員 口試委員-呂增宏
共同指導教授-張文昌
指導教授-洪建中
中文關鍵字 Sp1  breast cancer  vimentin 
英文關鍵字 Sp1  breast cancer  vimentin 
學科別分類
中文摘要 乳癌已經成為台灣女性發生率最高且死亡率第二高的癌症,乳癌病患十年存活率約為百分之六十,因此了解乳癌病程發展進而幫助藥物開發是有必要的。先前的研究已指出 Sp1 此屬於 specificity protein 家族中一員的轉錄因子會在許多癌化組織中過度表現,誘發我們想要探討Sp1在乳癌中所扮演的角色。上皮間質轉型 (Epithelial-mesenchymal transition, EMT) 對於胚胎型態發生以及傷口癒合皆是重要的機制,然而癌細胞也可藉由上皮間質轉型而獲得侵犯與轉移的能力。 Vimentin 是一個用來判斷間質細胞的重要標記,且具有高度表現vimentin 乳癌細胞的乳癌病患有著較差的預後,因此本篇研究目標為探討 Sp1 在乳癌轉移中所扮演的角色。首先,我們發現具有高度侵襲能力的 MDA-MB-231 乳癌細胞 Sp1 表現量低於不具侵襲能力的 MCF-7 乳癌細胞,而當我們在這兩株乳癌細胞過度表現 GFP-Sp1 後, MDA-MB-231 的細胞生長速率隨著 Sp1 的增加而增加,但 MCF-7 卻隨著 Sp1 增加而減少。我們更進一步發現隨著 Sp1 的增加, MDA-MB-231 的細胞移動能力明顯的降低,此外過度表現 GFP-Sp1 的 MDA-MB-231 細胞在免疫不全鼠中的轉移能力也明顯的下降,顯示過度表現 Sp1 具有抑制 MDA-MB-231 的轉移能力。在免疫組織染色和細胞實驗中,我們皆發現過度表現 GFP-Sp1 會導致 MDA-MB-231 乳癌細胞 vimentin 表現量的下降。我們發現過度表現 GFP-Sp1 可以明顯降低 MDA-MB-231 細胞對於 5’ flanking region (+165 ~ +1165) 的驅動能力,但對 promoter 區域 (-1~-1000) 卻沒有明顯的影響,顯示 Sp1 可以藉由抑制 5’ flanking region 而抑制 vimentin 的表現。但矛盾的是 vimentin 的 RNA 並沒有隨著 GFP-Sp1 過度表現而減少,顯示 Sp1 可能藉由影響其他如 vimentin 的轉譯 (translation) 機制而導致 vimentin 蛋白質表現量減少。我們在 MCF-7 此高度表顯 Sp1 但不表現 vimentin 的乳癌細胞中發現靜默 Sp1 並不能促使 vimentin 的表現量增加,且靜默 Sp1 會明顯降低含有 vimentin promoter 區域或 5’ flanking region 的 reporter 在 MCF-7 細胞中的表現,顯示 Sp1 在 MCF-7 細胞中可能扮演著正調控的角色,並且在不表現 vimentin 的 MCF-7 細胞中的環境對於 vimentin reporter plasmid 的驅動能力皆顯著的高於 MDA-MB-231 ,暗示著有著其他重要的機轉在抑制著 MCF-7 中 vimentin 的表現。接著我們利用 Sss I methyltranseferase 將 vimentin reporter plasmid 甲基化後發現在 MCF-7 細胞中對於 vimentin reporter plasmid 的驅動能力大幅的下降,顯示 vimentin 基因的甲基化可能是 MCF-7 細胞不表現 vimentin 的原因,因此我們希望在未來能找出 MCF-7 與 MDA-MB-231 這兩株乳癌細胞的 vimentin 基因中 -1000 ~ +1165 的區域的甲基化差異,進而解釋 MCF-7 不表現 vimentin 的原因。
英文摘要 In Taiwanese women, breast cancer has high incidence and mortality in all kind of cancers. Ten years survival rate of breast cancer patients is 60%, therefore understanding the mechanism of breast cancer progression is helpful for medicine development. Previous studies have found that specificity protein (Sp) 1 was overexpressed in many human cancers, for this reason, we are curious about whether Sp1 is relative to the metastasis of breast cancer. Epithelial-mesenchymal transition (EMT) is important for embryonic morphogenesis and wound healing, nevertheless, EMT enable cancer cells to acquire invasive and migratory ability. Vimentin is an important marker of mesenchymal cells, and breast cancer patients with high vimentin expression have poor prognosis. The objective of this study is to investigate whether Sp1 plays a critical role in regulating breast cancer metastasis. First, we found that MDA-MB-231 had lower Sp1 protein level than MCF-7. Moreover, proliferation of MDA-MB-231 was increased with increasing doses of GFP-Sp1 overexpression, whereas the proliferation of MCF-7 is decreased by Sp1. Furthermore, migratory ability of MDA-MB-231 was attenuated by GFP-Sp1 overexpression in a dose dependent manner. In addition, MDA-MB-231 overexpressing GFP-Sp1 exhibited a lower metastatic ability compared with GFP overexpressing cells in severe combined immunodeficient mice. To character how Sp1 repressed breast cancer metastasis, two experiments are proceeding. One is to study the effects of Sp1 in vimentin expression in breast cancer, and the other is to probe the gene expression profile of Sp1-overexpressing MDA-MB-231 globally by cDNA array. Up to now, our preliminary results indicated that Sp1 might be a negative regulator of vimentin expression in MDA-MB-231 cells, but not in MCF-7 cells. Moreover, vimentin promoter methylation also significantly decreased the transcriptional activity in MCF-7 cells, suggesting that multiple factors such as Sp1 or DNA methylation may determine the expression of vimentin. In addition, the global gene expression profile will provide us more information about the role of Sp1 in breast cancer progression. This study will clearly unravel the role of Sp1 in breast cancer, and might be benefit for the breast cancer therapy in the future.
論文目次 目錄
中文摘要 I
Abstract III
目錄 VI
圖目錄 VIII
縮寫檢索表 X
一、序論 1
第一節 前言 1
第二節 乳癌 1
第三節 Sp1 2
第四節 Vimentin 3
第五節 研究動機 4
二、實驗材料 6
三、實驗方法 13
四、實驗結果 25
第一節 乳癌細胞株中Sp1的表現差異 25
第二節 Sp1過度表現抑制乳癌細胞in vitro的侵犯能力 25
第三節 Sp1過度表現抑制乳癌細胞in vivo的侵犯能力 26
第四節 Sp1過度表現抑制乳癌細胞vimentin蛋白質表現 26
第五節 Sp1過度表現並不會抑制vimentin mRNA的表現 27
第六節 在MDA-MB-231細胞中Sp1抑制vimentin表現的詳細機轉 27
第七節 靜默Sp1不能使MCF-7細胞表現vimentin並且在MCF-7細胞中Sp1對於Vimentin 5’flanking region可能扮演著正調控的角色 28
第八節 Vimentin reporter plasmid在MCF-7細胞中具有高度活性 29
第九節 Vimentin RNA stability在MCF-7與MDA-MB-231細胞中沒有明顯的差異 29
第十節在MFC-7細胞中抑制vimentin表現的詳細機轉 30
五、實驗討論 32
第一節 Sp1如何降低vimentin表現而抑制MDA-MB-231乳癌細胞轉移 32
第二節 Sp1經由調控其他基因表現而抑制MDA-MB-231乳癌細胞轉移 32
第三節 Sp1在不同乳癌細胞中對vimentin扮演著不同角色 33
第四節 新穎性 34
參考文獻 35


圖目錄
Fig 1. Sp1 protein and RNA level in MCF-7 and MDA-MB-231 45
Fig 2. Proliferation of GFP-Sp1 overexpressing MCF-7 and MDA-MB-231 cells 46
Fig 3. Matrigel invasion assay of GFP-Sp1 overexpressing MDA-MB-231 cells 47
Fig 4. Transwell migration assay of GFP-Sp1 overexpressing MDA-MB-231 cells 48
Fig 5. Wound-healing migration assay of GFP-Sp1 overexpressing MDA-MB-231 cells 49
Fig 6. Overexpressing GFP-Sp1 MDA-MB-231 exhibited a lower metastatic ability 50
Fig 7. Immunohistochemical staining of lung sections of severe combined immunodeficient mice 51
Fig 8. Vimentin protein level in GFP-Sp1 overexpressing MDA-MB-231 cells 52
Fig 9. Vimentin mRNA level of GFP-Sp1 overexpressing MDA-MB-231 cells 53
Fig 10. The mRNA sequence and coding sequence of Human vimentin genomic sequence 54
Fig 11. Luciferase reporter assay of vimentin -1 ~ -1000 region and +165 ~ +1165 region in MDA-MB-231 cells 55
Fig 12. Luciferase reporter assay in GFP-Sp1 overexpressing MDA-MB-231 cells 56
Fig 13. Sp1 and vimentin protein level of Sp1-knockdown MCF-7 cells 57
Fig 14. Luciferase reporter assay in Sp1-knockdown MCF-7 cells 58
Fig 15. The transactivation ability of vimentin promoter in MCF-7 cell 59
Fig 16. Vimentin RNA stability and vimentin 3’UTR stability in MCF-7 and MDA-MB-231 cells 60
Fig 17. Methylation repress vimentin promoter activity in MCF-7 cells 61
Fig 18. The diagrams of CpG sites and putative Sp1 binding sites in vimentin -1000 to +1165 sequence 62
Fig 19. Methylation status of -214 ~ +212 region of vimentin genomic in MCF-7 and MDA-MB-231 cells 63
Fig 20. Working model 64
Appendix 1 65
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