臺灣博碩士論文加值系統

樟芝(Antrodia camphorata; AC)為台灣特有的藥用真菌，寄生於牛樟樹上，是常見的傳統中藥，目前對樟芝的研究已顯示具有抗發炎、抗氧化與抗腫瘤等功效。本實驗室已證實從樟芝發酵液獲得的AC-10能抑制MDA-MB-231乳癌細胞的生長，誘導乳癌細胞凋亡，但是AC-10對於抑制MDA-MB-231乳癌細胞轉移的相關機制仍不明確。癌細胞轉移的過程中通常伴隨著細胞外基質(Extracellular matrix; ECM)的分解，而主要扮演分解ECM的角色為基質金屬蛋白酶(Matrix metalloproteinase；MMPs)，以及促進MMPs活化的尿激酶原激活物(urokinase-type plasminogen activator ; uPA)。本研究先以MTT測試細胞存活率，在對於細胞較不具毒殺性且存活率皆大於80%以上的濃度下進行實驗。首先在細胞遷移試驗 (Wound migration assay)與細胞移行試驗 (Transwell invasion assay)方法中顯示，隨著0、20、40、60、80 μg/ml的AC-10濃度，可以抑制乳癌細胞的遷移和移行能力。另外，由西方墨點法結果顯示AC-10能降低MMP-9、MMP-2、uPA、uPAR與VEGF的蛋白表現，以及MMP-9與uPA的活性。AC-10也增加基質金屬蛋白酶抑制劑TIMP-1、TIMP-2與血漿纖溶酶原激活物抑制物PAI-1的表現。進一步探討訊息傳遞，AC-10可以降低ERK1/2、P38與JNK1/2的磷酸化，結果顯示加了ERK抑制劑UO126與P38抑制劑SB203580可以降低MMP-9表現，若再加上AC-10則能更顯著降低MMP-9的表現，但是在加了JNK抑制劑SP600125與AC-10後，雖然也有降低MMP-9的活性表現的趨勢，但是較不顯著。AC-10亦能降低NF-kB的活性表現，因此，本實驗在觀察細胞遷移與轉移相關蛋白的表現皆顯示AC-10具有降低乳癌細胞轉移的能力，且可能透過抑制ERK1/2、P38與JNK1/2路徑向下調控核內NF-kB表現，並影響MMP-9轉移因子的表現進而抑制乳癌細胞的轉移。

Antrodia camphorata (AC) is well- known in Tiawan as a traditional Chinese medicine. It has been shown to exhibit anti-inflammatory, antioxidation and anticancer properties. According to the previous data, AC-10 induced apoptosis in human breast cancer cells (MDA-MB-231). Breast cancer is a common cancer in women. In this study, we investigate anti-metastatic activity of AC-10. Degradation of extracellular matrix is crucial for malignant tumor development and metastasis. Treatment with AC-10 is effective in suppressing cancer cell migration and invasion. These effects were associated with a reduced protein expression of MMP-9, MMP-2, uPA, uPAR and VEGF together with an enhanced expression of TIMP-1, TIMP-2 and PAI-1. AC-10 decreased activities of MMP-9 and uPA, but not effect of MMP-2. Further studies showed that AC-10 regulated MMP-9 production via MAPK signaling pathway, as evidenced by the findings that AC-10 inhibited the phosphorylation of ERK1/2, P38 and JNK1/2. Additionally, pretreatment of MDA-MB-231 cancer cells with 10 and 30 μM of U0126, a specific ERK inhibitor, and SB203850, a specific P38 inhibitor and SP600125, a specific JNK inhibitr resulted in a reduced activities of MMP-9. And AC-10 inhibited NF-kB transcriptional activity. These results suggested that AC-10 could reduce the invasion and migration via MAPK and NF-kB signaling pathways in MDA-MB-231 human breast cancer cells, and may use AC-10 as an anti-invasive agent in the prevention and treatment of breast cancer.

謝誌…………………………………………………………………………V
縮寫表 ……………………………………………………………………VI
中文摘要 ……………………………………………………………… VIII
Abstract……………………………………………………………………X
第一章 緒論 ……………………………………………………………1
第一節 樟芝介紹 ……………………………………………………2
第二節 乳癌…………………………………………………………11
第三節 癌細胞轉移過程……………………………………………13
第四節 基質金屬蛋白酶與轉移的相關性…………………………15
第五節 基質金屬蛋白酶抑制劑與轉移的相關性…………………20
第六節 纖維蛋白溶解系統和轉移的相關性………………………20
第七節 血管新生與轉移的相關性…………………………………22
第八節 Mitogen-Activated protein Kinase ( MAPK )與轉移的相
關性…………………………………………………………23
第九節 Nuclear factor kappa B (NF-kB)與轉移的相關性………26
第十節 研究動機……………………………………………………29
第二章 實驗設計架構圖………………………………………………30
第三章 實驗器材………………………………………………………32
第四章 實驗方法………………………………………………………36
一、 樟芝發酵液 (AC-10)…………………………………………37
二、 細胞培養………………………………………………………37
三、 細胞存活率分析(Cell viability)………………………………38
四、 細胞遷移試驗(Wound migration assay)…………………… 39
五、 細胞移行試驗(Transwell invasion assay)……………………39
六、 MMPs活性分析(Gelatin zymography)………………………41
七、 uPA活性分析(Casein zymography)…………………………42
八、 西方墨點(Western blotting)分析法………………………… 43
九、 抑制劑之處理…………………………………………………48
十、 NF-kB活性測定(NF-kB reporter assay)……………………48
十一、 分析統計………………………………………………………49
第五章 實驗結果與圖表………………………………………………50
第一節 樟芝發酵液(AC-10)對MDA-MB-231細胞遷移情形與轉
移相關蛋白的表現 …………………………………………51
第二節 樟芝發酵液(AC-10)影響MDA-MB-231細胞的訊息傳遞
路徑與其可能調控的MMP-9表現 ………………………69
第六章 討論……………………………………………………………81
第七章 結論……………………………………………………………87
第八章 參考文獻………………………………………………………90
圖表目錄
圖 1-1. 樟芝型態…………………………………………………………2
圖 1-2. 樟芝子實體與菌絲體發酵液……………………………………6
圖 1-3. 乳癌分期 ………………………………………………………12
圖 1-4. 細胞外基質的組成 ……………………………………………14
圖 1-5. 癌細胞的轉移過程……………………………………………15
圖 1-6. MMPs的結構 …………………………………………………16
圖 1-7. 蛋白分解酵素分解細胞外基質相關機制 ……………………21
圖 1-8. VEGF促進血管新生與癌細胞轉移機制圖 …………………23
圖 1-9. MAPK與IkB影響NF-kB調控路徑 ………………………27
圖 1-10. NF-kB調控相關基因表現 ……………………………………28
圖 4-1. 轉移盤(Transwell) ……………………………………………41
圖 4-2. 蛋白質轉印 ……………………………………………………47
圖 5-1. 觀察AC-10對MDA-MD-231乳癌細胞存活率之影響………55
圖 5-2. AC-10對MDA-MD-231乳癌細胞遷移的影響………………56
圖 5-3. AC-10對MDA-MD-231乳癌細胞移行的影響………………57
圖 5-4. AC-10對MDA-MD-231細胞MMP-9和MMP-2蛋白表現 …58
圖 5-5. AC-10對MDA-MD-231乳癌細胞MMP-9和MMP-2的活性 59
圖 5-6. AC-10對MDA-MD-231乳癌細胞TIMP-1的蛋白表現………60
圖 5-7. AC-10對MDA-MD-231乳癌細胞TIMP-2的蛋白表現………61
圖 5-8. 觀察AC-10與Anti-TIMP-2抗體影響MDA-MD-231乳癌
細胞移行的現象 ………………………………………………62
圖 5-9. AC-10對MDA-MD-231乳癌細胞uPA的蛋白表現 …………64
圖 5-10. AC-10對MDA-MD-231乳癌細胞uPA的活性………………65
圖 5-11. AC-10對MDA-MD-231乳癌細胞uPAR的蛋白表現………66
圖 5-12. AC-10對MDA-MD-231乳癌細胞PAI-1的蛋白表現………67
圖 5-13. AC-10對MDA-MD-231乳癌細胞VEGF的蛋白表現 …68
圖 5-14. AC-10對MDA-MD-231乳癌細胞MAPK蛋白表現 ………72
圖 5-15. ERK抑制劑U0126與AC-10對MDA-MD-231乳癌細胞
MMP-9的蛋白表現 …………………………………………74
圖 5-16. ERK抑制劑U0126與AC-10對MDA-MD-231乳癌細胞
MMP-9的活性表現………………………………………… 75
圖 5-17. P38抑制劑SB203580與AC-10對MDA-MD-231乳癌細胞
MMP-9的蛋白表現………………………………………… 76
圖 5-18. P38抑制劑SB203580與AC-10對MDA-MD-231乳癌細胞
MMP-9的活性表現………………………………………… 77
圖 5-19. JNK抑制劑SP600125與AC-10對MDA-MD-231乳癌細胞
MMP-9的蛋白表現 …………………………………………78
圖 5-20. JNK抑制劑SP600125與AC-10對MDA-MD-231乳癌細胞
MMP-9的活性表現 …………………………………………79
圖 5-21. AC-10影響NF-kB的轉錄活性 ……………………………80
圖 7-1. 結論機制圖……………………………………………………89
表 1-1. Proximate composition in Antrodia camphorata ……………3
表 1-2. 三萜類及多醣體有效成份說明……………………………… 5
表 1-3. 乳癌的分期判斷………………………………………………12
表 1-4. MMPs的種類…………………………………………………19

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