臺灣博碩士論文加值系統

鐵對於細胞的增生是必需的，而過多的鐵也許會參與於肝癌的形成過程中。所以在本論文中，我便想要研究deferoxamine (DFO)對於人類肝癌細胞株HepG2的作用機轉。DFO是一種鐵螯合劑; DFO處理HepG2細胞之後，發現細胞的存活率與生長明顯隨著劑量增加而減少，而且經由DFO處理過的細胞也顯示出型態改變，包括：細胞體積變大、胞內顆粒與空泡增加，以流式細胞分析儀發現DFO會造成細胞週期中G1/S細胞增加，G2/M細胞減少。實驗也發現細胞處理25 micro M DFO之後，細胞核內的p53與p21蛋白質含量明顯隨投藥時間增加而增加；而由DFO引發的p53蛋白質表現量會被外加過氧化氫或鐵離子所阻擋。另一方面發現DFO處理HepG2細胞，會導致細胞內的過氧化自由基減少，但卻不會影響細胞內的超氧陰離子含量。為了更加肯定hypoxia-inducible factor（HIF）-1α在DFO引發p53表現的途徑中扮演之角色，實驗結果發現DFO會造成HepG2細胞內的HIF-1α蛋白質增加，而HIF-1α蛋白質的增加並不會被外加過氧化氫所阻擋。當實驗將DFO與另一個鐵螯合劑mimosine做一比較發現：這兩種藥物對於細胞內的p53、HIF-1α蛋白質的調控作用非常相似。使用流式細胞分析儀，更可進一步發現處理過25 micro M DFO的HepG2細胞18小時後，細胞膜上的輸鐵蛋白質接受器含量增加，這也代表著細胞呈現鐵耗盡的現象。這些結果顯示出（1）DFO引發G1/S細胞的堆積也許牽涉在依賴p53的途徑中（2）細胞內p53的增加與細胞內過氧化氫的減少有關（3）以DFO處理HepG2細胞後發現HIF-1α、輸鐵蛋白接受器明顯增加且HIF-1α的增加可能與穩定p53的表現有關。

Iron is required for cell proliferation and excess iron may be involved in the development of hepatocellular carcinoma. In this study, the effects of deferoxamine (DFO), an iron chelator, in human hepatoma HepG2 cells was investigated. DFO treatment dose dependently reduced the viability and cell growth of HepG2 cells. Moreover, DFO treated cells showed morphological changes including an increase of cell volume as well as intracellular granules. Flow cytometric analyses showed that DFO treatment resulted in an increase of cells in G1-S phase and a decrease of cells in G2-M phase. The levels of p53 and p21 proteins were significantly increased in a time dependent manner after treatment with 25 micro M DFO. The induction of p53 by DFO was abolished by hydrogen peroxide and ferric ammonium citrate. On the other hand, DFO treatment of HepG2 cells resulted in decreased intracellular hydrogen peroxide level with no change in superoxide level. In order to determine the role of hypoxia-inducible factor (HIF)-1α in mediating DFO induced up-regulation of p53, it was found that DFO treatment of HepG2 cells also resulted in increased level of HIF-1α. Moreover, to compare the effects of DFO to mimosine, a well-characterized iron chelator, it was found that both drugs similarly altered cellular levels of p53 and HIF-1α proteins. Using flowcytometry, it was further found that after treatment of HepG2 cells with 25 micro M DFO for 18hr, increased level of transferrin receptors was found on cell surface, indicating that the cells were iron-starved. These results demonstrated that (1) DFO induced accumulation of G1-S cells may involve a p53-dependent pathway (2) The induction of p53 appears to correlate with decreased level of intracellular hydrogen peroxide. (3) DFO treated HepG2 cells showed elevation of HIF-1α and transferrin receptor and the increase of HIF-1α may be involved in regulation of the expression of p53.

頁數
中文摘要…………………………………… 1
英文摘要…………………………………… 2
縮寫表……………………………………… 3
壹、 緒論
一、 細胞中鐵的功能………………………4
二、 鐵螯合劑簡介…………………………5
三、 鐵與癌症………………………………7
四、 癌症的形成、特性與治療……………8
五、 p53蛋白質與癌症……………………11
貳、實驗動機………………………………15
參、實驗目的………………………………16
肆、實驗藥品………………………………17
伍、研究方法及進行步驟…………………19
陸、結果……………………………………27
柒、討論……………………………………34
捌、結論……………………………………43
玖、參考文獻………………………………45
圖表…………………………………………61

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