臺灣博碩士論文加值系統

中文摘要
惡性腫瘤(癌症)已是國人死亡十大原因的首位，是影響國人健康的重要因素。癌症細胞的特性是以異常之速度分化成長，並能克服腫瘤體積增加導致之組織內部及細胞缺氧，而繼續存活生長。目前之研究顯示缺氧可造成缺氧誘發因子-1 alpha（hypoxia-inducible factor-1α, HIF-1α）之穩定/活化，HIF -1α可引起血管內皮生長因子(vascular endothelial growth factor, VEGF)之生成增加，進而誘發血管新生，此作用與腫瘤細胞之成長與侵犯性有關。除了誘發VEGF之表現外，HIF-1可以造成Transforming growth factor-α; (TGF-α)之釋出，進而作用在上皮成長因子接受器（epidermal grow -th factor receptor, EGFR），引起EGFR之活化，促進腫瘤細胞之增生與局部侵犯性。缺氧的另一個作用是增加活性氧分子之生成，即增加氧化壓力。近來之研究顯示活性氧分子可以活化許多轉錄因子（transcriptional factors），其中亦包含HIF-1之活化。而在許多腫瘤或非腫瘤細胞中發現氧化壓力之增加可誘發VEGF之表現、導致血管新生、TGF-α之釋放及EGFR之活化。因此，氧化壓力所導致之生物效應似乎與HIF-1活化所產生之作用相似。本研究即在探討頭頸部鱗狀細胞癌中，缺氧所導致之活性氧分子生成在活化IV
HIF-1與EGFR及癌細胞增生與侵犯性之角色。我們以不同的頭頸部鱗狀細胞癌細胞株進行研究。分別將三株不同之細胞株（FaDu、Detroit 562、Scc25）暴露於1%氧氣濃度下培養達24小時，並在不同時間點收集細胞，以NBT（Nitro blue tetrazolium）測量超氧游離基(superoxide;O2- )、DCFH-DA（2,7-dichloridihydrofluoresce – in diacetate）測量過氧化氫(H2O2)之生成，並以西方墨點法標定HIF-1α、活化態之EGFR，分析缺氧下HIF-1α、活化態EGFR的表現，以及在給予過氧化氫分解酶(catalase;CAT)後，HIF-1α蛋白質及活化態之EGFR的表現。結果發現在1%氧氣濃度培養下可造成各細胞株H2O2之生成增加，但superoxide(O2-)之生成則無顯著影響。缺氧亦可導致HIF-1α與EGFR之量隨缺氧暴露時間之增加而增加。H2O2之生成與HIF-1α之表現在缺氧3小時即有顯著增加，H2O2之生成在缺氧6小時達峰值，而HIF-1α之表現則於12小時達峰值。活化態EGFR之表現則在缺氧6小時才有顯著增加並維持至24小時。若在缺氧同時給予觸酶(catalase)，則可明顯抑制缺氧所導致HIF-1α與活化態EGFR之增加。此研究結果顯示，缺氧可造成頭頸部鱗狀細胞癌之H2O2之生成增加，此活性氧分子之增加在誘發HIF-1α與EGFR之活性上扮有重要的角色。

Abstract
Malignant tumor has been the leading causes of death in Taiwan for many years. Caner cells possess many special characteristics including rapid proliferation even in a hypoxia environment, a common feature found in the majority of human tumors resulting from tumors rapid growth and inadequate blood supply. Previous studies have showed that hypoxia causes the stability and activation of hypoxia inducible factor-1α(HIF-1α), which can induce the expression of vascular endothelia growth factor (VEGF). It is well known that VEGF plays an important role in angiogenesis and subsequently leads to tumors proliferation and invasion. In addition, HIF-1αalsoenhances the release of transforming growth factor-α(TGF-α) and binding and activation of epidermal growth factor receptor (EGFR). Several studies have demonstrated that activation of EGFR is associated with tumor cells proliferation and invasion. Another important finding is that the formation of reactive oxygen species (ROS) is also increased in response to hypoxia. Recently, many studies have reported that ROS can activate many transcriptional factors including HIF-1. Furthermore, ROS can induce the expression of VEGF, release of TGF-αand activation of EGFR in both tumor and non-tumor cells. These results suggest that the biological effects of ROS may be similar to that of HIF-1. Therefore, in the present study, we investigate the role of ROS induced by hypoxia on activation of HIF-1α
VI
and EGFR in head and neck tumor cells. Three tumor cells including FaDu, Detroit 562 and Scc25 were cultured in 1% O2 for different time period. The levels of superoxide anion (O2-) and hydrogen peroxide (H2O2) were measured by nitro blue tetrazolim (NBT) and 2,7-dichloridihydrofluorescein diacetate (DCFH-DA), respectively. The expression of HIF-1αand active form of EGFR was evaluated by Western blotting. Our results showed that incubation in hypoxia (1% O2 ) resulted in an increased formation of H2O2 but no significant difference of O2- production in all three types tumor cells compared with that of cells incubated in normoxia condition. Hypoxia also caused the induction of HIF-1αand EGFR in a time dependent manner. After hypoxia for 3 hrs, the H2O2 formation and HIF-1αexpression began to increase and reached the peak amount at hypoxia for 6 and 12 hrs, respectively. However, until hypoxia for 6 hrs the expression of active form of EGFR began to enhance and maintained for 24 hrs under hypoxia condition. Addition of catalase resulted in a significant inhibition of hypoxia-induced enhanced expression of HIF-1α and active form EGFR. These results showed that in head and neck tumor cells, hypoxia can increase H2O2 formation, which may play an important role in induction of HIF-1αand EGFR.

目錄
頁次
目錄 ………………………………………………………………… I
圖次 ………………………………………………………………… II
中文摘要 …………………………………………………………… IV
英文摘要 …………………………………………………………… VI
第一章緒論 ………………………………………………………… 1
第二章研究目的 …………………………………………………… 16
第三章實驗材料與方法 …………………………………………… 17
第四章實驗結果 …………………………………………………… 34
第五章結論 ………………………………………………………… 64
第六討論 …………………………………………………………… 65
第七章參考文獻 …………………………………………………… 71

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