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研究生:盧益靜
研究生(外文):Y.C. Lu
論文名稱:蕃茄素及蕃茄素定對人類腎細胞癌細胞株分泌介白素六之作用
論文名稱(外文):The Actions of Tomatine and Tomatidine on the Interleukin-6 Secretion from Human Renal Cell Carcinoma Cell Line – A498 and 786-O
指導教授:王錫五王錫五引用關係
指導教授(外文):Shyi-Wu Wang
學位類別:碩士
校院名稱:長庚大學
系所名稱:基礎醫學研究所
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:2007
畢業學年度:95
語文別:中文
論文頁數:106
中文關鍵詞:番茄素番茄素定腎細胞癌 介白素六
外文關鍵詞:renal cell carcinomaInterleukin-6Tomatine Tomatidine
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番茄素 (Tomatine) 與番茄素定 (Tomatidine) 為番茄中的成份之一,屬於類固醇醣基生物鹼 (Steroidal glycoalkaloid),廣泛地存在於茄科植物 (Solanum Plant) 的根、莖及葉片中,其中以根部的含量為最多。Tomatine 與Tomatidine的作用包括在腸內和膽固醇形成一不可吸收的複合物,影響膽固醇吸收及影響細胞膜的通透性,亦可作為疫苗之佐劑 (adjuvant),而增加其作用,此外亦可經由促進細胞凋亡,而抑制肝癌細胞的生長等。但其對於泌尿系統的癌症影響未知,腎細胞癌為泌尿系統中常見的癌症,其對於傳統的化學與放射線治療具高度的抗藥性。腎細胞癌可分泌細胞激素,其中介白素六(Interleukin-6, IL-6)為此癌細胞可高量分泌之細胞激素,其可促進癌細胞的生長,且病患血液中如有高量的IL-6,預後也較為不佳。因此本論文主要的目的即是探討Tomatine 與Tomatidine對於人類腎細胞癌細胞株─A498及786-O,分泌IL-6之影響。本計劃之假說為:Tomatine與Tomatidine可能經由JAK/STAT及MAPK等訊號傳遞路徑影響此兩個細胞株之IL-6 分泌,及IL-6 mRNA的表現。實驗結果顯示,Tomatine與Tomatidine於0.2 、10 μM/ml可抑制A498及786-O細胞IL-6的分泌及其IL-6 mRNA表現量。在藥物處理6小時其可顯著抑制IL-6的分泌,此作用持續12小時,而至24小時,IL-6之分泌則與未以藥物處理之細胞無顯著差異。在抑制IL-6 mRNA表現量方面,亦可觀察到隨藥物處理之時間及劑量的增加,此抑制現象也愈明顯。此外實驗結果亦發現Tomatine與Tomatidine可誘發ERKs 的磷酸化,並抑制STAT 3磷酸化,而以U0126抑制ERKs 磷酸化則可回復由Tomatine與Tomatidine所抑制之IL-6 mRNA表現量及STAT 3磷酸化。在細胞生長方面,Tomatine與Tomatidine處理72小時後,可觀察到細胞的生長隨藥物劑量的增加而顯著地減少。由實驗結果得知, Tomatine 及Tomatidine可抑制A498及786-O細胞分泌IL-6,並抑制其生長,而參與其中的訊號路徑則為促使ERK 1/2 磷酸化,且ERK 1/2 磷酸化會抑制STAT 3 之磷酸化。期望本實驗的結果對應用食物中之營養物質於腎細胞癌治療之研究上有所助益。
Tomatine and tomatidine are steroidal glycoalkaloids occurred in all parts of tomato plant, especially in green fruit. Previous studies showed that tomatine and tomatidine inhibit fungal infection, lower plasma cholesterol and triglycerides, enhance the immunity, anti-inflammation and induce cancer cell apoptosis. In addition, tomatine mixed with cholesterol can be used as a novel adjuvant for the induction of Th1 and Th2 cytokines secretion. However, the effects of tomatine and tomatidine on the urinary systems are still not clear. Several clinical and biological features suggest that cytokines implicated in the inflammatory response are produced by renal cell carcinoma. Interleukin-6 is produced at high levels by renal cell carcinoma and plays an important role in the biology. The effects of tomatine and tomatidine on the interleukin-6 (IL-6) secretion from renal cell carcinoma (RCC) cell lines A498 and 786-O, however, is still unknown. The aim of present study is to explore the effects of tomatine and tomatidine on the IL-6 secretion from RCC cell line–A498 and 786-O. Our results indicate that: (1) treatment of tomatine and tomatidine inhibit the secretion of IL-6 from A498 and 786-Ocells after 6 hours incubation; (2) attenuated IL-6 mRNA expression in does-dependent manner were observed in A498 and 786-O cells treated with tomatine and tomatidine; (3) elevated ERKs phosphorylation and inhibited phosphorylation of STAT3 were found in A498 and 786-O cells treated with tomatine and tomatidine; (4) IL-6 mRNA and phosphorylation of STAT3, however, were return to untreated levels in does-dependent of U0126,the inhibitor of MEK;(5)significant inhibitory effects of cell growth were observed in A498 and 786-O cell after treatment of tomatine and tomatidine. In conclusion, the inhibitory effect of tomatine and tomatidine on IL-6 secretion from A498 and 786-O is through the reduced IL-6 mRNA expression, activated of ERK1/2 phosphorylation and attenuated STAT3 phosphorylation. In addition, the inhibition of cell growth effect was also observed.
第一章 腎細胞癌 1
1.1 腎細胞癌介紹 1
1.2 腎細胞癌的危險因子 2
1.3 腎細胞癌之分級 3
1.4 腎細胞癌的臨床症狀 5
1.5 腎細胞癌的診斷 6
1.6 腎細胞癌的治療 7
1.7 腎細胞癌與細胞激素 9
第二章 番茄素 (Tomatine) 與番茄素定 (Tomatidine) 12
2.1番茄素(Tomatine)與番茄素定(Tomatidine)介紹 12
2.2 Tomatine與Tomatidine之作用 13
2.2.1 Tomatine 及Tomatidine 對於膽固醇吸收的影響 13
2.2.2 Tomatine 及Tomatidine對於細胞膜的影響 15
2.2.3 Tomatine 及Tomatidine對於免疫功能的影響 15
2.2.4 Tomatine 及Tomatidine對於癌細胞及細胞凋亡的影響 16
2.2.5 Tomatine 及Tomatidine抗黴菌感染之作用 17
第三章 實驗目的及假說 19
3.1目的 19
3.2假說 20
第四章 實驗材料 21
4.1 細胞株 21
4.1.1 細胞株的培養及冷凍與解凍 21
4.1.1.1 細胞株培養 21
4.1.1.2 冷凍細胞株 21
4.1.1.3 解凍細胞株 22
4.2 實驗儀器 22
4.3 實驗方法 23
4.3.1 酵素免疫測定法 (Enzyme-linked immunosorbent, ELISA) 23
4.3.2西方墨點法 (Western blot) 25
4.3.3反轉錄PCR(Reverse transcriptase-polymerase chain reaction, RT-PCR) 30
4.3.4 藥物毒性測試 ─ 乳酸脫氫酵素 (Lactic dehydrogenase, LDH) 34
4.3.5蛋白質濃度測定 (Protein assay) 35
4.3.6細胞計數 (Cell couter) 36
4.3.7數據分析 37
第五章 實驗結果 38
5.1 Tomatine 及Tomatidine抑制A498及786-O細胞分泌IL-6 38
5.2 Tomatine及Tomatidine對A498細胞毒性之測試 39
5.3 Tomatine及Tomatidine抑制A498及786-O細胞IL-6 mRNA 之表現 40
5.4 Tomatine及Tomatidine對A498及786-O細胞分泌IL-6 訊號傳遞之影響 42

5.4.1 Tomatine及Tomatidine可誘發A498及786-O細胞
ERKs之磷酸化 42

5.4.2 抑制ERKs磷酸化可回復Tomatine及Tomatidine對
A498細胞IL-6 mRNA之抑制 43

5.4.3 Tomatine及Tomatidine誘發ERKs磷酸化並抑制STAT3
磷酸化 43

5.4.4 Tomatine及Tomatidine抑制A498及786-O細胞的生長 45
第六章 討論 47
參考資料 54
圖誌 65
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