金屬蛋白酶調控細胞進展、功能、轉移與配體-受器交互作用。 其中ADAMs家族為一種跨膜蛋白，參與細胞膜上蛋白質切割作用，包含細胞激素與細胞激素受器。 MMPs則為基質金屬蛋白酶，功能為分解細胞外基質與活化生長因子，對腫瘤造成促進血管新生、腫瘤生長與轉移。 許多文獻指出金屬蛋白酶改變腫瘤微環境，促進腫瘤的進展與活化訊息傳遞路徑。 本論文分四部分探討白血病細胞之分子調控機轉，在研究中使用arecoline、hydroquinone、gallic acid與simvastatin，分析在血癌細胞K562中ADAM17、MMP-2與MMP-9之調控機制。 Arecoline為檳榔中的主要成分之一，已被證實具有致癌毒性、細胞毒性、免疫毒性與基因毒性。 實驗結果發現arecoline透過JNK/c-Jun刺激TNFR2 mRNA表現上升，並抑制ADAM17熟化作用，導致細胞表面TNFR2表現量增加，誘發透過TNFR2的細胞死亡。 Hydroquinone為苯在骨髓中的代謝產物，會導致骨髓細胞毒性與其他血液疾病。 Hydroquinone抑制miR-122表現而增加ADAM17 mRNA穩定性，使ADAM17在細胞表面大量表現，造成sTNF-α分泌增加。 Gallic acid為多羥基酚醛類化合物，存在於植物、水果與食物中，例如茶葉與莓果類，具有抗菌、抗發炎與抗癌活性。 實驗結果指出，Gallic acid誘導細胞中JNK的去活化調控c-Jun/ATF-2表現，並降低Akt/ERK調控的c-Jun/c-Fos，分別抑制了MMP-2與MMP-9的表現。 Simvastatin 為臨床上降低血中膽固醇用藥，用來預防冠狀動脈硬化。 先前研究指出simvastatin選擇性抑制MMP-9而非MMP-2表現，但調控機制尚未明確。 實驗結果指出，simvastatin降低NFκB穩定性，抑制MMP-9表現，但同時活化JNK/c-Jun/ATF-2路徑，平衡了MMP-2受NFκB的抑制作用。 了解調控ADAM17、MMP-2與MMP-9的分子機制以及在細胞中所扮演的角色，期許藉由調控金屬蛋白酶表現而對血癌的輔助治療上有進一步的幫助。

Metalloproteinases regulate aspects of cell development, effector function, migration, and ligand-receptor interactions. Membrane-anchored disintegrin metalloproteinases (ADAMs) are transmembrane proteins which carry out ectodomain shedding of cytokines and their congnate receptors. Matrix metalloproteinases (MMPs) became known as the primart class of enzymes responsible for degradation of extracellular matrix protein. The main role of MMPs in angiogenesis, tumor growth, and metastasis is degradation of extracellular matrix and release and/or activation of growth factors through their degradative activity. Mounting evidence supports the view that extracellular proteinases mediate many of the change in the microenviroment during tumor progression. These enzymes regulate a variety of physiological processes and signaling events, and thus they represent key players in the molecular communication between tumor and stroma. In this thesis, arecoline, hydroquinone, gallic acid, and simvastatin are employed to investigate the molecular mechanisms in regulating ADAM17 and MMP-2/MMP-9 of leukemic cell line K562. Arecoline is an alkaloid extracted form betel nuts. Arecoline have been shown to be characterized by carcinogenicity, cytotoxicity, immunotoxicity, and genotoxicity. Our data revealed that arecoline up-regulated transcriptional level of TNFR2 mRNA via JNK/c-Jun pathway activation in K562 cells. Moreover, arecoline-induced down regulation of mature ADAM17 reduced TNFR2 shedding. Up-modulation of TNFR2 surface expression is associated with arecoline-induced death of K562 cells. Hydroquinone, a major marrow metabolite of leukemogen benzene, leading to myelotoxicity and benzene-related hematogical disorders. Hydroquinone induced down-regulation of miR-122 expression, leading to ADAM17 up-regultion and ADAM17-mediated TNF-α shedding. Gallic acid as a polyhdyroyxlphenolic compound is widely distributed in various plants, fruits, and foods. Various biological activities of gallic acid have been reported, including antibacterial, anti-inflammatory, and anticancer activities. MMP-2 and MMP-9 downregulation in gallic acid treated K562 cells were mediated throuht suppression of JNK1-mediated c-Jun/ATF-2 and Akt/ERK-mediated c-Jun/c-Fos pathways, respectively. Simvastatin is commonly prescribed cholesterol-lowering drug that significantly improve the morbidity and mortality associated with atherosclerosis. Privious studies show that simvastatin selectively inhibit MMP-9 expression but not MMP-2 expression in cancer cells. However, the mechanism remains elusive. Our date indicated that simvastatin-induced NFκB degradation led to MMP-9 down-regulation, while simvastatin-induced JNK1/c-Jun/ATF-2 activation kept MMP-2 expression underlying NFκB down-regulation. This aim of the study is to interpret the role of ADAM17, MMP-2 and MMP-9 in leukemia cells, focusing especially on their poteintial use as cancer biomarkers and therapeutic target.

論文審定書 i
誌謝 ii
摘要 iii
Abstract iv
縮寫表 xiv
前言 1
金屬蛋白酶 (metalloproteinase) 1
白血病 (Leukemia) 5
研究材料與方法 10
實驗藥品 10
細胞培養 12
細胞藥物處理 12
細胞存活率測試 12
Annexin V-PI 雙染色 12
細胞內鈣離子濃度 13
西方點墨法 13
流式細胞儀分析細胞表面TNF-α、TNFR1、TNFR2、ADAM9、ADAM10及ADAM17表現 14
DNA細胞轉殖I (DNA transfection I) 14
DNA細胞轉殖 II與RNA Interference 14
利用ELISA測量游離型TNFR2 (sTNFR2)與TNF-α (sTNF-α) 15
RT-PCR及 Real-time PCR偵測TNF-α、TNFR1、TNFR2、MMP-2、MMP-9、ADAM17及miR-122表現 15
TNF-α與ADAM17 mRNA穩定性分析 16
染色質免疫沉澱分析 (Chromatin immunoprecipitation assay, ChIP) 16
TNFR2、TNF-α與pri-miR-122 promoter 選殖與冷光活性分析 18
細胞增生測試 19
DNA親和免疫沉澱分析 (DNA affinity purification assay, DAPA) 19
明膠基質金屬蛋白酵素活性測試 (Gelatin Zymography) 20
細胞移動試驗 (Cell migration assay) 20
細胞核質分離 20
統計分析 20
第一部分：檳榔鹼透過抑制細胞表面ADAM17與增加細胞表面TNFR2表現而誘導人類血癌細胞K562細胞死亡 22
研究背景 23
檳榔鹼 (Arecoline) 23
腫瘤壞死因子-α (TNF-α) 23
研究動機 25
結果 26
檳榔鹼(arecoline)增加K562細胞表面TNF-α、TNFR1及TNFR2蛋白質表現 26
檳榔鹼(arecoline)增加K562細胞內鈣離子濃度並影響MAPKs活性 26
JNK抑制劑(SP600125)影響arecoline誘導細胞表面TNF-α、TNFR1及TNFR2蛋白質表現量 27
分析檳榔鹼應答因子(arecoline-responsive element)對TNFR2與TNF-α基因啟動子之影響 27
Arecoline抑制金屬蛋白酶ADAM17對細胞表面TNF-α、TNFR1與TNFR2的切割作用 28
Arecoline增加K562細胞對TNF-α造成細胞死亡的敏感性 30
討論 31
第二部分：對苯二酚誘導miR-122表現下降因而增加ADAM17表現，造成在有表現Bcr/Abl的血癌細胞中，溶解性TNF-α產物釋放量增加 52
研究背景 53
對苯二酚 (Hydroquinone, HQ) 53
微型核糖核酸(MicroRNA) 53
研究動機 55
結果 56
Hydroquinone (HQ)透過轉譯後修飾調控游離性TNF-α (sTNF-α)分泌 56
HQ誘導ADAM17表現造成sTNF-α分泌增加 56
HQ藉由降低miR-122調控ADAM17表現量增加 57
HQ誘導p38 MAPK與JNK的活化，因而促進ADAM17 mRNA穩定性增加 57
p38 MAPK/JNK調控c-Jun、c-Fos與ATF-2活性，並抑制miR-122表現 58
表現Bcr/Abl融合蛋白質的血癌細胞中，HQ藉由下調miR-122與增加ADAM17表現調控sTNF-α的產量 59
討論 60
第三部分：Gallic acid透過調控Bcr/Abl導致人類血癌細胞MMP-2與MMP-9表現受抑制 84
研究背景 85
沒食子酸(Gallic acid) 85
研究動機 86
結果 87
Gallic acid抑制Bcr/Abl-positive細胞MMP-2與MMP-9表現 87
Gallic acid 透過Bcr/Abl調控MMP-2/MMP-9表現 87
Gallic acid透過Bcr/Abl調控Akt與MAPKs之活性 88
Gallic acid藉由Akt/ERK與JNK調控MMP-9與MMP-2 89
Gallic acid調控MMP-2與MMP-9啟動子冷光活性 90
Gallic acid其衍生物對MMP-2/MMP-9表現之影響 90
EGCG與quercetin對K562與U937其MMP-2/MMP-9之影響 91
討論 92
第四部份：在人類白血病細胞中，simvastatin藉由調控NFκB表現與JNK1/c-Jun/ATF-2活性，抑制基質金屬蛋白酶MMP-9但非MMP-2表現 109
研究背景 110
Simvastatin 110
Pin1 111
研究動機 113
結果 114
Simvastatin抑制K562細胞中MMP-9表現 114
Simvastatin導致NFκB蛋白質降解 114
Simvastatin降低Pin1表現而減少NFκB蛋白質穩定性 115
Simvastatin活化JNK、c-Jun與ATF-2導致NFκB調控的MMP-2表現回復 115
Bcr/Abl-positive與Bcr/Abl-negative血癌細胞在simvastatin處理下有相似的作用機轉 117
討論 118
總結 130
未來探討方向 134
附圖 137
參考文獻 145
發表著作目錄 179
會議發表著作 181

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