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系統識別號 U0026-0901201200301700
論文名稱(中文) 肝細胞生長因子及其受體於超細微碳黑粒子誘導人類肺腺癌細胞增生所扮演的角色
論文名稱(英文) The role of HGF/c-Met signaling in ultrafine carbon particles-induced proliferation of human pulmonary adenocarcinoma H441 cells
校院名稱 成功大學
系所名稱(中) 環境醫學研究所
系所名稱(英) Institute of Environmental and Occupational Health
學年度 100
學期 1
出版年 100
研究生(中文) 林憶慈
研究生(英文) Yi-Tsz Lin
學號 s7697109
學位類別 碩士
語文別 中文
論文頁數 62頁
口試委員 指導教授-張志欽
口試委員-劉明毅
口試委員-廖寶琦
中文關鍵字 超細微碳黑粒子  細胞增生  克氏細胞  肝細胞生長因子 
英文關鍵字 cell proliferation  Clara cell  HGF  c-Met  ultrafine nanoparticle 
學科別分類
中文摘要 先前研究指出暴露超細微碳黑粒子(Ultrafine carbon black, ufCB)能藉由表皮生長因子受體(EGFR)引發肺泡第二型上皮細胞的增生,本研究目的為探討超細微碳黑粒子誘發末梢支氣管上皮細胞肺腺癌克氏細胞株(Clara cells),以及瞭解肝細胞生長因子(HGF)與其受體(c-Met)之間調控細胞增生作用途徑為何。在實驗方法中利用人類肺腺癌克氏細胞株NCI-H441暴露超細微碳黑粒子來觀察細胞增生現象、c-Met及EGFR蛋白磷酸化、以及HGF於上清液中的表現量,此外,藉由添加HGF抗體、c-Met抑制劑(SU11274)及EGFR抑制劑(AG1478)來觀察於暴露ufCB後所引發的細胞增生現象,細胞於暴露完ufCB後收取上清液並偵測HGF的表現量,西方墨點法用來觀察暴露ufCB後c-Met及EGFR的訊號傳遞,而細胞免疫螢光染色用來觀察暴露ufCB後c-Met的磷酸化程度及HGF的表現量。本實驗結果顯示暴露ufCB後可引發NCI-H441的細胞增生現象,而暴露ufCB 24及48小時後藉由添加HGF抗體、SU11274及AG1478皆可有效降低H441細胞增生現象,此外,暴露超細微碳黑粒子24及48小時後亦可於細胞培養上清液中觀察到HGF表現量上升,並且添加抗氧化劑SOD可有效降低HGF的表現量,西方墨點法中則可於暴露ufCB不同時間點中觀察到c-Met於兩個小時表現量最高,而EGFR於四個小時表現量最高,除此之外,ERK1/2也於暴露ufCB後兩小時表現量最高,並且隨著添加SU11274不同劑量呈現劑量效應的下降趨勢。於實驗結論顯示,暴露超細微碳黑粒子可藉由c-Met訊號傳遞路徑誘發人類肺腺癌克氏細胞株的細胞增生現象,未來的研究當中將觀察暴露超細微碳黑粒子後c-Met及EGFR之間於細胞增生調控中的交互作用,以及利用人類肺腺癌細胞株H441暴露奈米微粒後同位移植入動物體內來觀察腫瘤發展現象。
英文摘要 Previous studies have shown that ultrafine particles can induce lung alveolar type II cell proliferation via epidermal growth factor receptor (EGFR). This study investigates the role of hepatocyte growth factor and it`s receptor (HGF/ c-Met) in ultrafine particle-induced proliferation of Clara cells. In vitro, Clara cells NCI-H441 were exposed to ufCB to examined cell proliferation, phosphorylation of c-Met and EGFR receptor and HGF production. Neutralizing anti-HGF antibody, Met kinase inhibitor SU11274 or EGFR kinase inhibitor AG1478 were applied to investigate the involvement of c-Met and EGFR in cell proliferation. The supernatant of ufCB-treated cells were collected for the measurement of HGF. Western blotting was used to delineate the activation of EGFR and c-Met signaling and immunofluorescence (IF) staining to investigate the phosphorylation of c-Met and expression of HGF following ufCB exposure. The result demonstrated that ufCB induced cell proliferation of NCI-H441 cells. Neutralizing anti-HGF antibody, SU11274 or AG1478 was able to reduce cell proliferation increased by ufCB exposure at 24 and 48 hrs in H441. HGF productions in the culture medium were significantly increased at 24 and 48 hrs and were significantly reduced by SOD pre-treatment. Time-dependent study revealed that ufCB exposure triggered the peak phosphorylation of c-Met at 2hrs, whereas that of EGFR at 4hr and ERK1/2 phosphorylation also showed that increased at 2hrs in a time-dependent study and could decrease significantly by pre-treat Met inhibitor SU11274 in inhibitor study. The results demonstrate that the activation of c-Met by ufCB plays important roles in pulmonary Clara cell proliferation. Future study will explore the interplay between c-Met and EGFR in ufCB-induced cell proliferation and orthotopic H441 cells after exposed ufCB to investigate tumor progression in animal study.
論文目次 中文摘要 i
Abstract ii
目 錄 iv
圖目錄 vi
第一章 研究背景 1
第二章 文獻探討 4
第一節 奈米微粒與健康效應 4
第二節 奈米微粒引發細胞增生重要性 8
2.2.1細胞激素的調節 8
2.2.2肺部上皮細胞的修復角色 11
第三節 肺部上皮細胞肺部所扮演之角色 13
2.3.1克氏細胞(Clara cells)於肺部所扮演的角色 13
2.3.2第二型上皮細胞於肺部所扮演的角色 14
2.3.3類幹細胞轉變成癌細胞之可能性 15
第三章 研究目的 17
第四章 材料與方法 18
第一節 材料 18
第二節 方法 19
4.2.1 細胞培養(Cell culture) 19
4.2.2 奈米碳黑微粒(Ultrafine carbon black)與炭黑微粒(N990)懸浮溶液 19
4.2.3 細胞增生(Cell proliferation assay) 19
4.2.4 西方墨點法(Western blotting assay) 20
4.2.5 Human HGF ELISA assay 21
4.2.6 Mouse HGF ELISA assay 21
4.2.7免疫螢光染色法 22
4.2.8 統計分析 23
第五章 實驗結果 24
第一節 奈米微粒誘發細胞增生作用 24
第二節 奈米微粒誘發細胞激素之釋放 25
第三節 奈米微粒誘發肝細胞生長因子訊息傳遞路徑 27
第四節 表皮生長因子的調控作用 29
第六章 討論 30
第七章 結論 34
第八章 未來研究方向 35
參考文獻 36
附錄、圖 48
附錄一 59
附錄二 61


圖目錄
圖1、細胞增生劑量與時間增生趨勢圖 48
圖2.1、HGF release 二十四小時趨勢圖 49
圖2.2、HGF release 四十八小時趨勢圖 49
圖3、HGF antibody抑制細胞增生趨勢圖 50
圖4、SU11274, PD98059抑制細胞增生趨勢圖 51
圖5.1、p-c-Met/t-Met蛋白表現量時間趨勢圖 52
圖5.2、p-ERK1/2/t-ERK1/2蛋白表現量時間趨勢圖 53
圖6、p-c-Met,,HGF細胞免疫螢光染色圖 54
圖7.1、SU11274抑制p-c-Met蛋白表現量圖 55
圖7.2、SU11274抑制p-ERK1/2蛋白表現量圖 56
圖8、AG1478抑制細胞增生圖 57
圖9、p-EGFR/t-EGFR蛋白表現量時間趨勢圖 58
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