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研究生:辛旻潔
研究生(外文):Min-Chie Hsin
論文名稱:穿山龍萃取物抑制人類子宮頸癌細胞轉移和侵襲之機制探討
論文名稱(外文):Study of the inhibitory effects of Dioscorea nipponica extracts on migration and invasion of cervical cancer cells
指導教授:楊順發謝逸憲
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2013
畢業學年度:101
語文別:中文
論文頁數:71
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根據世界衛生組織統計顯示,子宮頸癌 (cervical cancer) 是全球婦女第三常見的癌症,台灣也是高發生率國家之一。而造成子宮頸癌病患死亡的主因在於癌症轉移 (metastasis) 。在癌轉移中,腫瘤會釋出趨化因子、生長因子及基質金屬蛋白水解酶 (Matrix- metalloproteinase, MMP) 來分解細胞外基質 (extracellular matrix, ECM) 而形成血管新生,腫瘤因此藉由血液流動進而轉移到其他組織。穿山龍 (Dioscorea nipponnica) 是坊間廣為使用的中草藥,具降血壓及鎮咳功效。有許多文獻指出,穿山龍具有抗氧化、抗過敏、抗發炎及抗腫瘤等功效,但對於穿山龍是否可抑制子宮頸癌轉移與侵襲及其詳細機轉尚未釐清。因此本篇研究將探討穿山龍對子宮頸癌之抗癌效果及其中詳細機制為何。12-O-tetradecanoyl-phorbol-13-acetate (TPA) 也稱為PMA,是一種腫瘤促進因子,有研究指出TPA會誘發腫瘤細胞中MMP-9,使細胞轉移更為明顯。因此在本實驗中,我們使用TPA當作誘發因子並同時以50% 酒精萃取的穿山龍萃取物來處理HeLa細胞株。首先利用MTT 分析方法證實在本研究中使用之穿山龍萃取物濃度 (0、5、10、20 μg/mL) 並不會影響HeLa細胞株的存活率。接著由gelatin zymography assay結果發現穿山龍萃取物會抑制HeLa細胞中由TPA所誘發的MMP-9蛋白活性。進一步我們在Boyden chamber assay中觀察到穿山龍萃取物明顯抑制由TPA所誘發HeLa細胞的轉移及侵襲能力。因此我們推測,穿山龍萃取物可能藉由調控MMP-9的基因活性來抑制子宮頸癌細胞的轉移及侵襲。我們進一步以reverse-transcription PCR及real-time PCR發現穿山龍萃取物明顯抑制由TPA所誘發的MMP-9 mRNA表現。並且在Luciferase reporter assay中發現MMP-9啟動子活性確實受到穿山龍萃取物的抑制。另外在訊息傳遞路徑部分,我們利用Western blot方法發現TPA對HeLa細胞中MMP-9活性的調控是經由ERK1/2、JNK路徑。總結以上結果,我們發現在子宮頸癌細胞 (HeLa cell) 中,穿山龍萃取物可能透過抑制TPA所誘發的MMP-9表現使癌轉移能力降低,但其上游訊息傳遞路徑有待再進一步實驗確認。除此之外,穿山龍萃取物對MMP-9轉錄因子的調控也需要以ChIP assay來找出其詳細的調控機制。

According to World Health Organization (WHO) statistics, cervical cancer is the third common cancer of women in the world, and also exhibits a high rate in Taiwan. Cervical cancer patients died primarily because of cancer metastasis. During cancer metastasis, the extracellular matrix (ECM) was decomposed by cancer-released chemokines, growth factors and matrix metalloproteinases (MMPs), and further promote cancer angiogenesis and distal metastasis through blood flow. Dioscorea nipponnica was a popular folk medicine with several proven biological benefits including reducing blood pressure and anti-allergy, anti-inflammation and anti-tumor. However, the anti-metastatic effects and the underlying mechanisms of this medicine on cervical cancer cell were still unclear. 12-O-tetradecanoyl-phorbol-13-acetate (TPA) is a tumor promoter and may induce the activity of MMP-9 in cancer cells. In this study, simultaneous treatment of an inducer, TPA, and 50% alcohol-extracted Dioscorea nipponnica. At First, from MTT assay result, we found that the concentrations we used in this study did not affect the viability of HeLa cells. The DNE also inhibits TPA-induced migration and invasion, as shown by results of the Boyden chamber assay. Moreover, we found that Dioscorea nipponnica extract (DNE) suppresses TPA-induce matrix metalloproteinase-9 (MMP-9) expression in human cervical cancer HeLa cell. Therefore, we hypothesized that the DNE may inhibit TPA-induced migration and invasion through the inhibition of MMP-9 activity. Furthermore, results from reverse-transcription PCR/real-time PCR and Luciferase assay indicated that DNE significantly inhibits TPA-induced MMP-9 mRNA expression and the promoter activity. Furthermore, results from western blot showed that DNE also inhibits the TPA-induced phosphorylation of ERK and JNK. In conclusion, DNE may inhibit TPA-induced migration and invasion through suppressing MMP-9 in human cervical cancer HeLa cell, but the detail underlying mechanisms remains to be confirmed in the future work.

中文摘要 1
英文摘要 3
縮寫表 5

第一章 緒論 7
1. 子宮頸癌 (Cervical cancer) 7
2. 中草藥介紹 (Introduction of traditional Chinese medicine) 15
3. 癌症轉移之特性 (The characteristics of cancer metastasis) 17
4. 基質金屬蛋白水解酶及基質金屬蛋白水解酶抑制劑 (Matrix
metalloproteinase, MMP / Tissue inhibitor of matrix
metalloproteinase, TIMP) 18
5. 12-O-tetradecanoylphorbol-13 acetate (TPA) 23
6. 研究動機 (Motive) 24

第二章 材料與方法 26
1. 實驗材料與配製方法 (Materials and methods) 26
2. HeLa細胞培養 (HeLa cell culture) 32
3. 穿山龍之萃取 (Extract from Dioscorea nipponica) 34
4. 細胞存活率測試 (Analysis of cell viability) 35
5. 體外腫瘤轉移性試驗 (Tumor metastasis assay in vitro) 36
6. 受質十二烷基硫酸鈉聚丙醯胺膠體電泳 (Substrate SDS-PAGE) 37
7. 反轉錄-聚合酶連鎖反應 (Reverse-transcription PCR) 39
8. 螢光素酶報導基因分析 (Luciferase reporter assay) 40
9. 西方墨點法 (Western blot) 41
10. 統計分析 (Statistical analysis) 43

第三章 結果 44
1. TPA及穿山龍萃取物對於人類子宮頸癌細胞 (HeLa cell) 之細胞存活率影響 44
2. 穿山龍萃取物對TPA在人類子宮頸癌細胞 (HeLa cell)中所誘發之細胞轉移與侵襲影響 44
3. 穿山龍萃取物對於TPA在人類子宮頸癌細胞 (HeLa cell)中所誘發之MMP-9酵素活性影響 45
4. 穿山龍萃取物對於TPA在人類子宮頸癌細胞 (HeLa cell)中所誘發之MMP-9 mRNA表現量之影響 46
5. 穿山龍萃取物對於TPA在人類子宮頸癌細胞 (HeLa cell)中所誘發之MMP-9 mRNA表現量之影響 (Real time PCR) 46
6. 穿山龍萃取物對於TPA在人類子宮頸癌細胞 (HeLa cell) 所誘發之MMP-9 基因上啟動子活性之影響 46
7. 穿山龍萃取物對於TPA在人類子宮頸癌細胞 (HeLa cell) 所誘發ERK、JNK與P38磷酸化表現之影響 48

第四章 討論 49
參考文獻 55
圖表與圖表說明 64


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