臺灣博碩士論文加值系統

乳癌為全球女性最常見的惡性腫瘤，癌細胞轉移是導致乳癌患者死亡的主要原因。臨床研究發現乳癌病人中約有20~30%具有致癌基因ErbB2的過度表現，其臨床預後差且存活率低。先前研究證實，乳癌細胞發生轉移與否和尿激酶型血纖維蛋白溶解酶原活化因子(Urokinase plasminogen activator, uPA)及基質金屬蛋白酶(Matrix metalloproteinases; MMPs)蛋白質表現與活性的增加有關。另有研究證實EGF可透過活化EGFR/ErbB2，正向調控ErbB2過度表現型SK-BR3人類乳腺癌細胞uPA、MMP-1和MMP-9表現。許多文獻指出，增加二十二碳六烯酸(docosahexaenoic acid, DHA; 22:6n-3)攝取可降低乳癌發生率並改善乳癌預後。雖有不少研究證實DHA具有抑制乳癌細胞轉移能力，但對於抑制SK-BR3乳癌細胞轉移機制仍不清楚。本研究以SK-BR3乳癌細胞為實驗模式，探討DHA對EGF誘發SK-BR3乳癌細胞之EGFR及ErbB2磷酸化與蛋白質表現，及其下游相關訊號路徑所調控uPA、MMP-1及MMP-9酵素活性與蛋白質表現之影響。實驗結果顯示，隨著EGF處理濃度與時間增加，顯著誘發uPA、MMP-1及MMP-9之酵素活性與蛋白質表現，處理DHA (100 μM)可負向調控EGF (40 ng/ml)所誘發uPA、MMP-1及MMP-9之酵素活性與蛋白質表現。DHA可顯著抑制EGF所誘發ERK1/2、JNK、Akt (Ser473)磷酸化，而且細胞預處理EGFR磷酸化抑制劑AG1478也可顯著降低EGF所誘發ERK1/2、JNK、(Ser473)磷酸化。此外，以EGF處理SK-BR3乳癌細胞15分鐘後，即顯著誘發EGFR及ErbB2磷酸化；而EGFR及ErbB2蛋白質表現量亦會隨EGF處理時間增加而增加。一旦加入DHA則可抑制EGF短時間所誘發EGFR及ErbB2磷酸化並降低EGF長時間所誘發EGFR及ErbB2蛋白質表現。免疫螢光染色法與共同免疫沉澱分析法結果顯示，DHA可顯著降低EGF所誘發SK-BR3細胞EGFR與ErbB2蛋白結合並減少胞內分佈。綜合上述結果，DHA經由抑制SK-BR3乳癌細胞之EGFR及ErbB2磷酸化與蛋白質表現與EGFR依賴的ERK、JNK、Akt (Ser473)訊號路徑，進而負向調控EGF所誘發uPA、MMP-1及MMP-9表現，達到抑制SK-BR3乳癌細胞轉移。

Breast cancer is the most commonly diagnosed cancer among women all over the world. Metastasis is the leading cause of death from breast cancer. EGFR and ErbB2 are an important oncogene overexpressed in about 20~30% of breast cancers, and was associated with poor patient outcome and distant metastasis. Previous study showed the induction of urokinase plasminogen activator (uPA) and matrix metalloproteinase (MMP)-1 and MMP-9 activity and expression were associated with breast cancer metastasis. EGF up-regulated uPA, MMP-1, MMP-9 expression by activating EGFR/ErbB2 in ErbB2-overexpressing SK-BR3 breast cancer cells. Diets consisting mostly of docosahexaenoic acid (DHA) have shown to reduce breast cancer incidence rate and have better outcomes There have been several studies on the role of DHA in suppressing breast cancer metastasis,however, the mechanism for the down-regulation of SK-BR3 breast cancer metastasis by DHA is not fully clarified. In the present study, we used ErbB2-overexpression SK-BR3 breast cancer cells to study the effect of DHA on EGF-induced EGFR/ErbB2 expression and activation, and further to investigate whether their downstream signaling pathways are involved in DHA''s down-regulation of EGF-induced MMP-1/-9 and uPA expression in SK-BR3 human breast cancer cells. We found that EGF (40 ng/ml) induced MMP-1, MMP-9, and uPA mRNA, protein expression and enzyme activity in both dose- and time-dependent manners, and 100 μM DHA significantly inhibited the induction of EGF. DHA was shown to inhibit EGF-induced activation of ERK1/2, JNK and Akt (Ser473). AG1478, a tyrosine kinase inhibitor of the EGFR, attenuated ERK1/2, JNK and Akt (Ser473) activation as well. The phosphorylation of EGFR and ErbB2 was induced within 15 min after EGF treatment and the total amount of protein was found to increase after 12 h of EGF exposure and these induction were decreased by DHA. Immuno-fluorescence assay and co-immuno-precipitation analysis showed DHA decreases EGFR expression and intracellular localization in the presence of EGF as well as the interaction between EGFR and ErbB2 was disrupted by DHA. These results suggest that attenuation of EGFR and ErbB2 expression and disruption of protein interaction between EGFR and ErbB2 and EGFR-dependent signaling pathways (ERK1/2、JNK、Akt (Ser473)) are involved in DHA''s down-regulation of EGF-induced MMP-1/-9 and uPA expression in SK-BR3 human breast cancer cells.

目錄 I
圖目錄 IV
表目錄 VI
縮寫表 VII
中文摘要 IX
英文摘要 XI
第一章 文獻回顧 1
一、乳癌現況 1
二、乳癌 1
1. 何謂乳癌 1
2. 乳癌病理 1
3. 乳癌分型 2
三、人類上皮生長因子受體 4
1. HER家族簡介 4
2. HER家族成員與配體 5
3. HER及其下游訊號傳遞路徑 6
四、EGFR/ErbB2與乳癌 8
五、癌症生成與癌細胞轉移 8
1. Carcinogenesis 8
2. Metastasis 9
3.尿激酶型血纖維蛋白溶解酶原活化因子 11
3.1.調控uPA基因表現之訊號傳遞路徑與轉錄因子 12
3.2. uPA和乳癌細胞轉移 13
4.基質金屬蛋白酶 14
4.1.調控MMP-1及MMP-9表現之訊號傳遞路徑與轉錄因子 16
4.2. MMP-1及MMP-9和乳癌細胞轉移 18
六、多元不飽和脂肪酸 19
1. n-3及n-6 PUFAs之生理作用 20
2. n-3 PUFAs抑癌機轉 21
3. n-3 PUFAs與乳癌 23
第二章 研究動機 24
第三章 實驗材料與方法 25
一、研究架構 25
二、實驗材料 26
三、實驗方法 33
1. 細胞培養 33
2. 細胞存活率分析 34
3. 細胞處理與蛋白質製備 35
4. 蛋白質定量 36
5. 西方點墨法 36
6. 共同免疫沉澱分析法 37
7 Casein-plasminogen/Gelatin zymography 38
8.RNA萃取與定量 39
9. Reverse Transcription-Polymerase Chain Reaction (RT-PCR) 40
10. Real-time Quantitative Polymerase Chain Reaction
(Real-time PCR) 40
11. Boyden chamber assay 41
12. 免疫螢光染色法 43
13. 統計分析 43
第四章 研究結果 44
一、不同劑量的DHA、AG1478與EGF對SK-BR3乳癌細胞存活率
之影響 44
二、EGF對誘發SK-BR3乳癌細胞之uPA、MMP-1及MMP-9
表現之影響 44
三、EGF對SK-BR3乳癌細胞ERK1/2、JNK1/2、P38及Akt蛋
白質磷酸化之影響 45
四、MAPK及PI3K/Akt訊號傳遞路徑在EGF誘發uPA、MMP-1及
MMP-9表現所扮演之角色 46
五、DHA對EGF誘發SK-BR3乳癌細胞之uPA、MMP-1及
MMP-9表現及其相關訊號傳遞路徑之影響 46
六、DHA對EGF誘發SK-BR3乳癌細胞移行及侵襲之影響 47
七、EGF對誘發SK-BR3乳癌細胞之EGFR及ErbB2磷酸化
與蛋白質表現之影響 47
八、DHA對EGF誘發SK-BR3乳癌細胞之EGFR及ErbB2磷酸化
與蛋白質表現之影響 48
九、DHA對SK-BR3乳癌細胞之EGFR及ErbB2蛋白質穩定性之影響 48
十、DHA對EGF誘發SK-BR3乳癌細胞之EGFR蛋白質表現
與分佈 49
十一、DHA對EGF誘發SK-BR3乳癌細胞之EGFR及ErbB2蛋白質
交互作用之影響 49

第五章 討論 72
第六章 結論 79
附錄一 SDS-PAGE配方 81
附錄二 0.2% CASEIN-8% SDS配方 82
附錄三 0.1% GELATIN-8% SDS配方 83
附錄四 REAL-TIME PCR所使用之基因序列 84
附錄五 PCR MIXTURE配方 85
文獻參考 86



圖目錄
文獻回顧
圖一、乳癌亞型的分類 3
圖二、HER結構HER活化型；受配體活化，形成複合體 5
圖三、HER成員與配體 6
圖四、活化HER與其下游訊息傳遞路徑 7
圖五、癌細胞轉移的主要過程 10
圖六、Plasminogen活化過程中，uPA之功能與調控 12
圖七、uPA基因之轉錄因子結合區 13
圖八、MMP-1及MMP-9基因之轉錄因子結合區 17
圖九、n-3及n-6 PUFAs合成eicosanoids之代謝圖 21
圖十、n-3 PUFAs影響胞內相關之訊息傳遞及轉錄因子 22

圖表結果
圖一、不同劑量DHA、AG1478與EGF對SK-BR3乳癌細胞存活率
之影響 51
圖二、不同劑量EGF處理對誘發SK-BR3乳癌細胞之uPA、
MMP-1及MMP-9表現之影響 52
圖三、不同EGF處理時間對誘發SK-BR3乳癌細胞之uPA、
MMP-1及MMP-9表現之影響 54
圖四、EGF處理短時間對誘發SK-BR3乳癌細胞之訊號傳遞路徑
之影響 56
圖五、EGF合併處理激酶抑制劑對誘發SK-BR3乳癌細胞
之uPA、MMP-1及MMP-9表現之影響 57
圖六、預處理不同劑量DHA對EGF誘發SK-BR3乳癌細胞
之uPA、MMP-1及MMP-9表現之影響 59
圖七、預處理DHA及EGFR磷酸化抑制劑對EGF誘發SK-BR3
乳癌細胞之訊號傳遞路徑之影響 61
圖八、預處理DHA及EGFR磷酸化抑制劑對EGF誘發SK-BR3
乳癌細胞移行及侵襲之影響 62
圖九、EGF處理短時間對誘發SK-BR3乳癌細胞EGFR及ErbB2
磷酸化之影響 65
圖十、不同EGF處理時間對誘發SK-BR3乳癌細胞之EGFR及
ErbB2蛋白質表現之影響 66
圖十一、預處理DHA及EGFR磷酸化抑制劑對EGF誘發SK-BR3
乳癌細胞EGFR與ErbB2磷酸化之影響 67
圖十二、預處理不同劑量DHA對EGF誘發SK-BR3乳癌細胞
之EGFR及ErbB2蛋白質表現之影響 68
圖十三、在CHX作用下，DHA不同處理時間對SK-BR3乳癌細胞
之EGFR及ErbB2蛋白質表現之影響 69
圖十四、預處理DHA對EGF誘發SK-BR3乳癌細胞之EGFR蛋白質
表現與分佈 70
圖十五、預處理DHA對EGF誘發SK-BR3人類乳腺癌細胞
之EGFR及ErbB2蛋白質交互作用之影響 71

結論
圖一、DHA抑制EGF所誘發SK-BR3乳癌細胞之uPA、MMP-1
及MMP-9表現進而負向調控癌細胞轉移之路徑圖 79


表目錄
文獻回顧
表一、乳癌亞型之特點 4
表二、基質金屬蛋白酶之分類 16

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