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系統識別號 U0026-2608201014005900
論文名稱(中文) 介白素十九與乳癌的研究
論文名稱(英文) Study of IL-19 and breast cancer
校院名稱 成功大學
系所名稱(中) 生物化學暨分子生物學研究所
系所名稱(英) of Biochemistry and Molecular Biology
學年度 98
學期 2
出版年 99
研究生(中文) 詹千慧
研究生(英文) Chien-Hui Chan
學號 s1697405
學位類別 碩士
語文別 中文
論文頁數 74頁
口試委員 指導教授-張明熙
口試委員-張敏政
口試委員-鄭宏祺
中文關鍵字 介白素  乳癌  轉移 
英文關鍵字 interleukin  berast cancer metastasis 
學科別分類
中文摘要 介白素-19是介白素-10家族中的一員,主要是由單核球所分泌。目前已知介白素-19參與許多發炎反應疾病的病程,像是牛皮癬、氣喘以及類風濕性關節炎等。近幾年,有越來越多的研究指出癌細胞本身分泌的細胞激素可以影響腫瘤的生長。在實驗室先前的研究也發現,在乳癌病人的組織切片上可偵測到介白素-19的存在。然而IL-19在乳癌中扮演的角色目前仍尚未清楚,因此,我們想要去探討介白素-19與乳癌之間的關聯性為何。在臨床統計數據顯示,介白素-19在乳癌病人中表現量的多寡與乳癌細胞是否有轉移的現象以及病人存活率的高低都有正向的相關性。在實驗上,首先,我們利用免疫組織染色法分別在4T1這株小白鼠的乳癌細胞上偵測到介白素-19以及其兩個受體的蛋白質表現。在細胞增生能力分析結果發現介白素-19可以促進4T1細胞的生長,也會誘導細胞內STAT3,NF-κB,Erk1/2,Jnk以及Akt等訊息傳遞分子的磷酸化。而在細胞遷徙能力的實驗中,我們觀察到介白素-19會促進4T1細胞的遷移能力。另外,介白素-19也會促進4T1細胞內一些與發炎反應(TGF-β,IL-1β,IL-6)或癌細胞轉移相關(MMP-2,MMP-9,CXCR4)基因的表現量上升。同時,我們也發現,在缺氧的條件下介白素-19可以調控CXCR4的基因表現。介白素-19也會促進4T1及Hs578T細胞表面纖連蛋白(Fibronectin)的組裝;而當利用EIPA抑制了細胞表面纖連蛋白的組裝後,再加入的介白素-19則亦可以再恢復部分表面纖連蛋白的組裝。為了更證明介白素-19與纖連蛋白的關係,我們利用siRNA抑制細胞介白素-19的表現後,發現細胞表面纖連蛋白的組裝也跟著被抑制。而在動物實驗中也可以觀察到,介白素-19的抗體,1BB1,可以藉由降低介白素-19的表現進而抑制腫瘤細胞的生長。基於以上的實驗結果,我們證明介白素-19在乳癌的致病過程中扮演重要的角色。
英文摘要 Interleukin (IL)-19, a member of IL-10 family, was mainly produced by monocytes. IL-19 was involved in the pathogenesis of various inflammatory diseases such as psoriasis, asthma and rheumatoid arthritis. Cytokines produced by cancer cells affected the growth of tumors. Previous study showed that IL-19 was expressed in several types of malignant tumors such as breast cancer. However, the biological functions of IL-19 in breast cancer were not well understood. In this study, we aimed to investigate the association of IL-19 with breast cancer in vitro and in vivo. In clinical data, IL-19 expression was associated with metastasis and disease-free survival in breast cancer. First, Immunohistochemistry (IHC) staining showed that IL-19 and its receptors were expressed in 4T1, a mouse breast cancer cell line. MTT assay showed that IL-19 promoted the proliferation of 4T1 cells. IL-19 also induced phosphorylation of STAT3, NF-κB, Erk1/2, Jnk and Akt in 4T1 cells. Boyden chamber assay revealed that IL-19 increased the migration of 4T1 cells. IL-19 induced the expression of metastasis-associated genes (CXCR4, MMP-2, MMP-9) and pro-inflammatory cytokines (TGF-β, IL-1β, IL-6) using real-time PCR analyses. IL-19 also regulated CXCR4 mRNA expression in hypoxia condition. In addition, IL-19 promoted fibronectin assembly on cell surface of suspended 4T1 cells and the human breast cancer cell line Hs578T. Fibronectin assembly decreased after treatment of EIPA (Na+/H+ exchanger inhibitor). Treatment of IL-19 could rescue EIPA-decreased fibronectin assembly on cell surface. Knockdown of IL-19 expression inhibited fibronectin assembly on suspended 4T1 cells. These results suggested that IL-19 may be involved in metastasis of breast cancer cells through inducing cell migration and upregulating the expression of metastasis-associated genes. Furthermore, anti-IL-19 antibodies, 1BB1, inhibited 4T1 tumor growth and metastasis in vivo. Our study provide new evidence that IL-19 is involved in the pathogenesis of breast cancer.
論文目次 中文摘要 1
英文摘要 2
致謝 3
目錄 5
圖目錄 8
表目錄 9
附錄目錄 10
縮寫檢索表 11
第一章 緒論 13
1-1 細胞激素 13
1-2 IL-10家族與IL-19 14
1-3 IL-19與疾病 15
1-4 乳癌 16
1-5 細胞激素與乳癌的關聯性 17
第二章 研究動機與目的 19
第三章 實驗方法與材料 20
3-1 實驗材料 20
3-1-1 細胞株來源及背景 20
3-1-2 蛋白質來源 20
3-1-3 實驗動物來源 20
3-1-4 專一性抗體來源 20
3-1-5 化學物品及特殊實驗用品來源 22
3-1-6 各種試劑配置 22
3-1-7 實驗使用儀器 24
3-2 實驗方法 26
3-2-1 免疫細胞化學染色法(Immunohistochemistry) 26
3-2-2 細胞增生能力分析(Cell proliferation assay) 26
3-2-3 細胞內訊息傳遞分析(Cellular signal transduction) 26
3-2-4 西方點墨法(Western blotting) 27
3-2-5 細胞遷徙能力分析(Cell migration assay) 27
3-2-6 同步定量聚合酶鏈鎖反應 28
(Real Time Polymerase Chain Reaction,Real Time-PCR)
3-2-7 懸浮細胞表面纖連蛋白螢光染色 29
(Suspended Cell surface fibronectin staining)
3-2-8 短暫性基因沉默(Transient gene knockdown)29
3-2-9 細胞內染色(Intracellular staining)29
3-2-10 動物實驗(Animal experiment) 30
3-2-11 酵素連結免疫吸附分析法 30
(Enzyme-linked immunosorbent assay;ELISA)
第四章 實驗結果 32
4-1 IL-19在乳癌組織的表達量與臨床結果呈正相關 32
4-2 4T1細胞可以表達IL-19以及其受體IL-20R1及IL-20R2 32
4-3 IL-19可以促進4T1細胞的細胞增生能力 32
4-4 IL-19可以誘發4T1細胞內訊號傳遞分子的磷酸化 33
4-5 IL-19可以促進4T1細胞的遷徙能力 33
4-6 IL-19可以促進4T1細胞內MMP-2即MMP-9的mRNA表現 33
4-7 IL-19可以促進4T1細胞內CXCR4的表現 34
4-8 在缺氧(Hypoxia)條件下,IL-19可以調控4T1細胞內CXCR4的
mRNA表現 34
4-9 IL-19可以促進4T1及Hs578T細胞表面纖連蛋白的組裝 35
4-10 IL-19可以促進4T1細胞內IL-1β、IL-6以及TGF-β的表現 36
4-11 IL-19的抗體能抑制老鼠腫瘤的生長 36
第五章 討論 37
參考文獻 41
實驗結果圖表 48
表格 65
附錄 66
自述 74
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