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dc.contributor.advisor蔣丙煌(Been-Huang Chiang)
dc.contributor.authorYi-Chien Fuen
dc.contributor.author傅一茜zh_TW
dc.date.accessioned2021-06-16T17:14:16Z-
dc.date.available2020-08-17
dc.date.copyright2012-08-27
dc.date.issued2011
dc.date.submitted2012-08-18
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dc.identifier.urihttp://tdr.lib.ntu.edu.tw/jspui/handle/123456789/63578-
dc.description.abstract肝素酶(Heparanase)為一種葡萄醣醛酸內切酶(endo-beta-D-glucuronidase),具有切割基底細胞膜與組織硫酸肝素鍵結的能力,可以在原位瘤發生惡化時促進腫瘤細胞轉移,且造成腫瘤細胞周遭微環境變化,對於癌症發生的進程有極大的影響。本研究即利用體外細胞模式,以共培養技術,模擬癌症細胞遭受腫瘤微環境因子影響而發生癌症轉移的現象,並以此平台探討植化素(phytochemicals)之介入對目標蛋白(Heparanase)及下游蛋白Akt, Src, MMPs之作用。本研究第一部分,探討以不同條件PMA誘導THP1細胞分化為polarized M2巨噬細胞的效果,發現以320 nM PMA處理 24小時可表現6.6%的polarized M2巨噬細胞表面抗原,並將此細胞在不同時間點(15-240分鐘)誘導HCT116大腸癌細胞株,發現在誘導時間內皆可促使HCT116細胞發生轉移性,其中又以30分鐘及120分鐘共培養效果最佳。第二部分介入文獻中提出具有抑制癌細胞轉移功效的植化素,在測試其對HCT116細胞毒性及酵素活性之影響後,篩選出五種具有潛力之植化素,進入第三部分的西方點墨法分析。結果顯示,以Quercetin及Resveratrol兩者具有最好的抑制轉移效果。在肝素酶蛋白表現上,以後介入方式施予Quercetin,具有抑制HPA酵素蛋白表現的功效,且有濃度效應,而在p-Src與p-Akt方面,以前介入或後介入方式皆有抑制的效果,而Resveratrol在Heparanase蛋白表現上並無抑制作用,但其可影響Heparanase下游蛋白Akt與Src,使其磷酸化降低,而達到抑制轉移的現象。總括而言,Quercetin為七種植化素中擁有最佳抑制轉移的能力,可以在細胞模式中經由抑制誘發的HCT116肝素酶表現,達到抑制癌症轉移的效果。zh_TW
dc.description.abstractHeparanase is a type of endo-beta-D-glucuronidase which can cleave heparan sulfate (HS) chains both at the cell surface and in the extracellular matrix. The enzyme is secreted by metastatic tumor cells, destroys surrounding tissue, and alters the microenviroment of the cells. In this study, we used an in vitro cell model which is established by co-cultivation of cancer cells and the tumor microenvironment factors. Then, we investigated the effect of some phytochemicals on the metastasis of the cancer cells. The first part of this study used different concentration of PMA to induce differentiation of THP1 cells to polarized M2 macrophage, and found that 320 nM PMA increase 6.6% polarized M2 cell’s surface antibody. After that, we used the polarized M2 macrophage to induce HCT116 cell at different time points to establish the metastasis mode. We found that the induction occurred at 30 minute and 120 minute resulted in the highest degree of metastasis. In the second part of this study, we first investigated the effects of the some potential phytochemicals on the cell survival rate anden
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Previous issue date: 2011
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dc.description.tableofcontents謝誌 I
中文摘要 IV
圖次 IX
表次 XI
壹、緒論 1
一、大腸直腸癌 1
(一)人類大腸直腸癌(colorectal cancer)之特性 1
(二)大腸直腸癌治療方式 4
(三)大腸直腸癌致癌機轉研究 7
(四)腫瘤微環境與癌症發展之關係 10
二、肝素酶 10
(一)肝素酶(Heparanase)簡介 10
(二)肝素酶表現於臨床病例增加癌症轉移 11
(三)肝素酶於細胞試驗增進血管新生與侵襲、轉移 12
(四)肝素酶與大腸直腸癌的關係 12
三、腫瘤相關巨噬細胞 13
(一)腫瘤相關巨噬細胞(tumor-associated macrophage, TAM)簡介 13
(二)腫瘤相關巨噬細胞促進腫瘤細胞侵襲與轉移 15
(三)腫瘤相關巨噬細胞增進腫瘤細胞血管新生 16
(四)腫瘤相關巨噬細胞與大腸直腸癌轉移關係 17
(五)以PMA誘導單核球細胞THP1分化成腫瘤相關巨噬細胞 17
四、植化素(phytochemicals) 19
(一)植化素簡介 19
(二)植化素的生理機能活性 19
貳、研究目的與實驗架構 23
一、研究目的 23
二、實驗架構 24
第一部分、建立評估轉移試驗的細胞模式 24
第二部分、篩選植物化學物質 25
第三部分、肝素酶於大腸癌細胞誘導轉移的影響與作用原理 26
参、材料與方法 27
一、實驗材料 27
(一)細胞株來源 27
(二)藥品試劑 27
(三)儀器設備 29
二、實驗方法 31
(一) 細胞培養(cell culture) 31
(二) 樣品配製 32
(三) 細胞存活率(MTT assay) 32
(四) 酵素活性試驗(b-D-glucurosidase active assay) 34
(五) PMA (Phorbol-12-myristate-13-acetate)誘導單核球細胞分化為巨噬細胞 ……………………………………………………………………………………………………………..36
(六) 流式細胞儀檢測巨噬細胞表面標記 37
(七) 巨噬細胞與大腸癌細胞共培養 38
(八) 轉移試驗(Migration assay) 40
(九) 蛋白質萃取與定量 42
(十) SDS-PAGE電泳分析 43
(十一)西方點墨法(Western blotting) 45
(十二) 酵素免疫分析(Enzyme-linked immunosorbent assay, ELISA) 46
(十三) 統計分析(Statistics analysis) 47
肆、結果與討論 48
一、單核球細胞株THP1經不同PMA濃度誘導產生的型態變化 48
二、單核球細胞株THP1經不同PMA濃度誘導分化為M2 macrophage (Tumor associated macrophage, TAM) 50
三、大腸癌細胞HCT116與320 nM PMA誘導M2細胞共培養 52
四、植化素對人類大腸直腸癌細胞株HCT116存活率之影響 55
五、以Migration assay 初步檢測各植化素在此模式中的抑制效果 58
六、利用西方點墨法探討經M2 Macrophage誘導之人類大腸癌細胞株HCT116肝素酶之表現 64
七、利用西方墨點法探討經M2 Macrophage誘導之 HCT116細胞之 Heparanase相關蛋白質之表現 66
八、Quercetin對M2巨噬細胞誘導轉移之HCT116細胞之HPA相關蛋白質表現之影響 71
(一) Heparanase(HPA)蛋白表現量 73
(二) Src與p-Src蛋白表現量 75
(三) Akt與p-Akt蛋白表現量 77
(四) MMP-2與MMP-9蛋白表現量 78
九、Resveratrol對M2巨噬細胞誘導轉移之HCT116細胞之 HPA相關蛋白質表現之影響 81
(一) Heparanase (HPA)蛋白表現量 81
(二) Src與p-Src蛋白表現量 83
(三) Akt與p-Akt蛋白表現量 85
(四) MMP-2與MMP-9蛋白表現量 85
伍、結論與展望 90
陸、參考文獻 91
附錄期刊格式 105
dc.language.isozh-TW
dc.subjectHCT116zh_TW
dc.subject腫瘤相關的巨噬細胞zh_TW
dc.subject肝素&#37238zh_TW
dc.subject癌症轉移zh_TW
dc.subject腫瘤微環境zh_TW
dc.subjectheparanaseen
dc.subjectTumor associated macrophageen
dc.subjectmetastasis canceren
dc.title植化素經由抑制肝素酶活性對預防大腸直腸癌轉移之功效zh_TW
dc.titleAnti-metastasis effect of phytochemicals on colorectal cancer cells via heparanase inhibitory activityen
dc.typeThesis
dc.date.schoolyear100-2
dc.description.degree碩士
dc.contributor.oralexamcommittee鐘景光(Jing-Gung Chung),何其儻(Chi-Tang Ho),吳明賢(Ming-Shiang Wu)
dc.subject.keyword肝素&#37238,腫瘤相關的巨噬細胞,癌症轉移,HCT116,腫瘤微環境,zh_TW
dc.subject.keywordheparanase,Tumor associated macrophage,metastasis cancer,en
dc.relation.page113
dc.rights.note有償授權
dc.date.accepted2012-08-20
dc.contributor.author-college生物資源暨農學院zh_TW
dc.contributor.author-dept食品科技研究所zh_TW
顯示於系所單位:食品科技研究所

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