臺灣博碩士論文加值系統

基質金屬蛋白酶(matrix metalloproteinases，簡稱MMPs)在腫瘤的侵襲和轉移方面扮演著重要的角色，他們可以分解細胞外基質和基底膜，使癌細胞得以滲入血管或組織中。MMPs中的明膠酶(gelatinases)，包括MMP-2與MMP-9，其主要作用是降解基底膜中的type IV膠原蛋白，在基底膜的破壞過程中扮演著重要角色，與癌症的侵犯及轉移關係密切。近年來的研究也陸續發現在口腔癌中MMP-2與MMP-9的表達扮演著舉足輕重的角色。然而，對於明膠酶在口腔癌癌化過程中的系列性變化還沒有完整的研究。因此，本實驗的目的是利用以二甲基苯駢蒽(9,10-dimethyl-1,2-benz[a]anthracene，簡稱DMBA)誘發的敘利亞倉鼠頰囊袋表皮樣癌模型(Syrian hamster cheek pouch model)來探討，在口腔癌癌化的過程中，MMP-2與MMP-9隨著時間的改變所產生的系列性變化。本實驗共用三十五隻敘利亞倉鼠，七隻為一組，分別在塗抹實驗的四、六、八、十、十二週犧牲，分別施以蘇木精與嗜伊紅染色(Hematoxylin-Eosin stain，簡稱H&E染色)與MMP免疫組織化學染色(immunohistochemistry stain，簡稱IHC染色)，以光學顯微鏡觀察，此外，取頰囊袋的組織進行明膠酶譜(gelatin zymography)觀察，並經AlphaImager 2000 densitometer定量後以簡單線性迴歸(simple linear regression)分析。實驗結果顯示，MMP-2在上皮細胞的基底細胞層(basal layer)與棘皮層(stratum spinosum)有表達；而MMP-9則在上皮細胞的基底細胞層、棘皮層以及顆粒層(stratum granulosum)有表達。明膠酶譜的結果，則顯示MMP-2及MMP-9的表達有隨時間增強的趨勢。進一步以統計方法分析發現，MMP-2和MMP-9表達的程度和塗抹實驗的時間呈正相關(p<0.05)。綜合本實驗的結果，敘利亞倉鼠口腔頰囊袋表皮樣癌模型可說是觀察口腔癌癌化過程系列性變化的良好模型，而明膠酶在口腔癌癌化過程的系列性變化中隨時間變化而增強的表達，則可能是口腔癌變化的良好指標。

Objective: The matrix metalloproteinases (MMPs) are produced by the cancer cells or through induction of surrounding stromal cells. The ability of gelatinase (MMP-2 and MMP-9) to degrade basement membrane type IV collagen appears especially important in cancer progression. However, the sequential alteration of gelatinases in oral carcinogenesis has not yet been well demonstrated. The aim of this study was to investigate the sequential gelatinases alteration in 9,10-dimethyl-1,2-benz[a]anthracene (DMBA)-induced hamster cheek pouch model. Methods: Thirty-five out-bred, young (7 weeks old), male Syrian golden hamsters were randomly divided into 5 experimental groups (week 4, 6, 8, 10, and 12 DMBA treated groups; each with 5 animals) and two control groups (5 animals each). The pouches of each experimental group were bilaterally painted with a 0.5% DMBA solution three times a week. Each animal of one control group was similarly treated with mineral oil only, while the other control group remained untreated throughout the experiment. All pouches were studied both grossly and histologically. Tissues from each group were used to evaluate MMP-2 and MMP-9 activities by gelatin zymography. Results: The main gelatinase secreted by hamster cheek pouch migrated at 72/92 kDa and represented MMP-2/MMP-9. The values of gelatinase activity were found increased in a time-dependent manner (p<0.05). From the AlphaImager 2000 densitometer, the amount of MMP-2/MMP-9 was about 1.4/1.0 fold on week 4 (hyperkeratosis), 1.6/1.0 fold on week 6 (hyperkeratosis and dysplasia), 1.7/1.8 fold on week 8 (verrucous hyperplasia and dysplasia), 2.0/6.1 fold on week 10 (para-hyperkeratosis and dysplasia), and 3.7/3.0 fold on week 12 (carcinoma) compared with control, respectively. Conclusion: These results demonstrate that the up-regulation of gelatinases expression in DMBA-induced oral carcinogenesis, suggesting that gelatinases may play an important role in the pathogenesis of oral cancer.

目錄••••••••••••••••••••••••••••••••••••••••••••••••••••••1
圖目錄••••••••••••••••••••••••••••••••••••••••••••••••••••2
壹、中文摘要•••••••••••••••••••••••••••••••••••••••••••••••4
貳、英文摘要•••••••••••••••••••••••••••••••••••••••••••••••6
參、文獻回顧•••••••••••••••••••••••••••••••••••••••••••••••8
肆、研究目的••••••••••••••••••••••••••••••••••••••••••••••31
伍、實驗材料與研究方法••••••••••••••••••••••••••••••••••••32
陸、實驗結果••••••••••••••••••••••••••••••••••••••••••••••49
柒、討論••••••••••••••••••••••••••••••••••••••••••••••••••57
捌、參考文獻••••••••••••••••••••••••••••••••••••••••••••••61
玖、圖片••••••••••••••••••••••••••••••••••••••••••••••••••78
圖目錄
圖一 正常倉鼠頰囊袋外觀••••••••••••••••••••••••••••••••••78
圖二 塗抹DMBA四週倉鼠頰囊袋外觀•••••••••••••••••••••••79
圖三 塗抹DMBA六週倉鼠頰囊袋外觀•••••••••••••••••••••••80
圖四 塗抹DMBA八週倉鼠頰囊袋外觀•••••••••••••••••••••••81
圖五 塗抹DMBA十週倉鼠頰囊袋外觀•••••••••••••••••••••••82
圖六 塗抹DMBA十二週倉鼠頰囊袋外觀•••••••••••••••••••••83
圖七 正常倉鼠頰囊袋H&E染色(200倍率) ••••••••••••••••••••84
圖八 塗抹DMBA四週倉鼠頰囊袋H&E染色(200倍率) ••••••••••85
圖九 塗抹DMBA六週倉鼠頰囊袋H&E染色(200倍率) ••••••••••86
圖十 塗抹DMBA八週倉鼠頰囊袋H&E染色(200倍率) ••••••••••87
圖十一 塗抹DMBA十週倉鼠頰囊袋H&E染色(200倍率) ••••••••88
圖十二 塗抹DMBA十二週倉鼠頰囊袋H&E染色(200倍率) ••••••89
圖十三 正常倉鼠頰囊袋MMP-2染色(200倍率) ••••••••••••••••90
圖十四 塗抹DMBA四週倉鼠頰囊袋MMP-2染色(200倍率) •••••91
圖十五 塗抹DMBA六週倉鼠頰囊袋MMP-2染色(200倍率) •••••92
圖十六 塗抹DMBA八週倉鼠頰囊袋MMP-2染色(200倍率) •••••93
圖十七 塗抹DMBA十週倉鼠頰囊袋MMP-2染色(200倍率) •••••94
圖十八 塗抹DMBA十二週倉鼠頰囊袋MMP-2染色(200倍率) •••95
圖十九 正常的倉鼠頰囊袋MMP-9染色(200倍率) •••••••••••••96
圖二十 塗抹DMBA四週倉鼠頰囊袋MMP-9染色(200倍率) •••• 97
圖二十一 塗抹DMBA六週倉鼠頰囊袋MMP-9染色(200倍率) •• 98
圖二十二 塗抹DMBA八週倉鼠頰囊袋MMP-9染色(200倍率) •• 99
圖二十三 塗抹DMBA十週倉鼠頰囊袋MMP-9染色(200倍率) ••100
圖二十四 塗抹DMBA十二週倉鼠頰囊袋MMP-9染色(200倍率) 101
圖二十五 倉鼠頰囊袋組織分泌的MMPs之明膠酶譜•••••••••••102
圖二十六 MMP-2明膠酶分解活性量化圖••••••••••••••••••••••103
圖二十七 MMP-9明膠酶分解活性量化圖••••••••••••••••••••••104
圖二十八 MMP-2明膠酶分解活性與時間之關係••••••••••••••••105
圖二十九 MMP-9明膠酶分解活性與時間之關係••••••••••••••••106

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