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研究生(外文):Mei-Ying Chen
論文名稱(外文):Identification of E2F4 Downstream Genes Involved in Tumor Invasion
指導教授(外文):Ling-Ling Chueh
外文關鍵詞:tumor invasionE2F4microarray
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E2F4為E2F家族中的一員,E2F依其功能可分為三組,其中E2F1、E2F2、E2F3其功能為促使細胞通過細胞週期(Cell Cycle)的G1期,進而促使細胞增值;另一組為E2F4及E2F5則與抑制細胞增值使細胞停滯在G1或G0期有關。文獻中指出E2F1具間接影響腫瘤侵入能力,在過去的實驗中我們發現具有高轉移性之子細胞株其內源性E2F4的表現量越低,反之E2F1的蛋白質表現量並沒有隨著侵入能力之差異而有明顯的變化。為了進一步了解E2F1與E2F4對於腫瘤細胞侵入能力的影響,我們以HeLa細胞株分別建立過量表現E2F1及E2F4進行侵入和移行實驗,實驗結果得知帶有大量表現E2F1的細胞株並未明顯增加其侵入及移行的能力,而在大量表現E2F4的細胞株侵入能力降低。為了瞭解E2F4表現時所啟動的下游基因,利用生物晶片(Microarray)分析Hela/E2F4.7及Hela/PCINeo兩株細胞株,我們挑選了Up-regulated 的DAB2、UCHL1基因,Down-regulated 的p53、KRT8、CTGF及MDK基因,以半定量RT-PCR確認生物晶片(Microarray)之結果。up-regulated 基因中,DAB2為腫瘤抑制基因,DAB2與UCHL1兩者皆與細胞週期相關;而KRT8、CTGF及MDK這些Down-regulated基因皆與腫瘤侵入、轉移、血管生成等機制相關。該結果顯示,E2F4在腫瘤侵入的過程中調控扮演抑制者的角色。

E2F4, a member of the E2F family of transcription factors, is abundant in non-proliferating and differentiated cells where it plays an important role in the suppression of proliferating associated genes. Several lines of evidence indicate that E2F1 is involved in neoplastic development, while little is known about E2F4 in tumor formation. Based on our previous study, the expression level of E2F1 was found not significantly associated with the progressiveness of more invasive sublines, while E2F4 showed progressively decreased. Stable clones overexpressing E2F1 in HeLa showed no significantly enhanced migration and invasion potential. However, when overexpressing E2F4, the tumor cells were found with reduced invasion potentials. In order to identify the down stream gene involved in the inhibition of tumor invasion in E2F4, Microarray analysis has been adapted to detect differentially expressed in Hela/E2F4.7 and Hela/PCINEO. The up-regulation of UCHL1 and DAB2 and the down-regulation of P53, KRT8, CTGF and MDK were observed. The differential expression of genes in Hela/E2F4.7 and Hela/PCINEO were confirmed by Semi-Quantitative RT-PCR analysis. The up-regulated genes are both cell cycle related, DAB was a tumor suppressor gene. The down-regulated genes are either tumor invasion, metastasis or angiogenesis associated. The potential roles of E2F4 expression in tumor metastasis were discussed.
Table of Contents

Table of Contents ……………………………………………………………………I
Abstract ………………………………………………………………………………Ⅱ
中文摘要 ……………………………………………………………………………Ⅲ
Introduction…………………………………………………………………………… 1
Specific aims ……………………………………………………………………… 25
Materials and Methods…………………………………………………………… 26
Results ……………………………………………………………………………36
Discussion ……………………………………………………………………………57
Future prospectiv………………………………………………………………… 68
Reference …………………………………………………………………………71

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