臺灣博碩士論文加值系統

軟骨肉瘤是一種惡性的腫瘤，具有高度侵入及遠端轉移的能力且偏愛轉移至肺部。趨化素配體2 (Chemokine ligand 2, CCL2) 又稱為單核球趨化蛋白 (Monocyte chemoattractant protein-1, MCP-1)，屬於CC趨化素中的一員與疾病及癌症的形成相關。然而，CCL2對於人類軟骨肉瘤細胞爬行的機制仍未明瞭。在這研究中，我們發現在人類軟骨肉瘤細胞中，CCL2會誘導人類軟骨肉瘤細胞爬行及基質金屬蛋白酶-9 (Matrix metalloproteinase-9, MMP-9) 表現，加入趨化素配體接受器2 (Chemokine receptor 2, CCR2)、Ras、Raf-1及MEK的抑制劑，可以有效抑制CCL2所增加軟骨肉瘤細胞的爬行及MMP-9的表現。CCL2刺激可活化Ras、Raf-1、MEK、ERK及NF-κB訊息，而給予Ras、Raf-1、MEK、ERK及NF-κB的專一性抑制劑和mutant則可抑制CCL2所誘導的細胞爬行及MMP-9表現。由實驗結果我們發現CCL2會活化Ras、Raf-1、MEK、ERK及NF-κB促使MMP-9的表現進而誘導軟骨肉瘤細胞的爬行。

Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. Chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1), belongs to the CC chemokine family that is associated with the disease status and outcomes of cancers. However, the effect of CCL2 on migration activity in human chondrosarcoma cells is mostly unknown. Here we found that CCL2 increased the migration and expression of matrix metalloproteinase (MMP)-9 in human chondrosarcoma cells. CCL2-mediated migration and MMP-9 up-regulation were attenuated by CCR2, Ras, Raf-1, and MEK inhibitor. Activation of the Ras, Raf-1, MEK, ERK, and NF-κB signaling pathway after CCL2 treatment was demonstrated, and CCL2-induced expression of MMP-9 and migration activity were inhibited by the specific inhibitor, and mutant of Ras, Raf-1, MEK, ERK, and NF-κB cascades. Taken together, our results indicated that CCL2 enhances the migration of chondrosarcoma cells by increasing
MMP-9 expression through the CCR2 receptor, Ras, Raf-1, MEK, ERK, and NF-κB signal transduction pathway.

目錄 I
圖目錄 V
縮寫對照表 VII
中文摘要 IX
英文摘要 X
壹、 緒論 9
一、 軟骨肉瘤 (Chondrosarcoma) 9
二、 轉移 (Metastasis) 14
三、 基質金屬蛋白酶 (Matrix metalloproteinases, MMPs) 21
四、 趨化素 (Chemokine) 29
五、 趨化素配體2 (Chemokine ligand 2, CCL2) 32
六、 Ras/Raf-1/MEK/ERK pathway 36
貳、 研究架構與動機 43
一、 研究背景 43
二、 研究目的 44
三、 研究假設 44
叁、 材料與方法 45
一、 實驗材料 45
第一節、 試劑與材料 45
(一)、實驗細胞 45
(二)、試劑 45
A. 實驗藥品 45
B. 細胞培養試劑 45
C. 電泳及西方墨點轉漬試劑 (Western blotting) 45
D. 抗體 (Antibody) 46
E. 即時聚合酶連鎖反應 (Quantitative Real-Time PCR, qPCR) 46
F. 細胞轉染法 (Cell transfection) 47
G. 染色質免疫沉澱技術 (Chromatin Immunoprecipitation, ChIP) 47
I. 細胞移行實驗 (Cell migration assay) 47
J. 電泳酵素分析法 (Zymography) 47
K. 其他藥品 48
(三)、 實驗儀器與耗材 48
第二節、 實驗方法 49
(一)、細胞培養 (Cell culture) 49
(二)、細胞爬行實驗 (Migration assay) 50
(三)、西方點墨法 (Western blotting) 51
(四)、即時聚合酶連鎖反應 (Quantitative Real-Time PCR) 52
(五)、細胞轉染法 (Transfection) 54
(六)、電泳酵素分析法 (Gelatin zymography) 55
(七)、冷光活性測試 (Luciferase reporter gene assay) 56
(八)、分析爬行實驗 (Wound-healing migration assay) 56
(九)、免疫螢光實驗 (Immunofluorescence) 57
(十)、染色質免疫沉澱法 (Chromatin Immunoprecipitation assay) 57
(十一)、 Ras 活性測試 (Ras kinase assay) 59
(十二)、統計方法 59
肆、 結果 61
一、 CCL2增加人類軟骨肉瘤細胞爬行 61
二、 CCL2會經由MMP-9促使人類軟骨肉瘤細胞爬行 61
三、 CCL2經由CCR2受器促使人類軟骨肉瘤爬行 62
四、 CCL2經由Ras及Raf pathway增加人類軟骨肉瘤細胞爬行 63
五、 CCL2經由MEK及ERK增加人類軟骨肉瘤細胞爬行 64
六、 CCL2調控NF-κB促使MMP-9表現上升及細胞的爬行 65
伍、 討論 67
陸、 結論 71
柒、 文獻 72
捌、 圖表 95

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