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研究生(外文):Pei-Ling Chiu
論文名稱(外文):The roles of IFIT2 expression in Epithelial-Mesenchymal Transition in Oral Squamous Cell Carcinomas
指導教授(外文):Te-Chang Lee
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根據流行病學資料顯示,口腔鱗狀上皮癌病患遍及全球。於2008年根據我國行政院衛生署統計口腔鱗狀上皮癌位居國人癌症死亡率第六位,更高居男性癌症死亡率第四位。表皮間質轉化過程對於表皮細胞轉化為間質細胞在細胞型態中扮演重要角色。正常生理功能中,表皮間質轉化過程常見於胚胎發育; 近年研究更將表皮間質轉化過程視為癌症轉移的起始步驟。可受到干擾素的誘導表現的IFIT2 基因,也被稱為干擾素誘導基因,於先前實驗室的研究中被發現其高表現量與口腔鱗狀上皮癌症病患有較佳的預後相關性。同時,其研究也發現,藉由抑制此基因在口腔鱗狀上皮細胞株的表現會增加細胞的移動能力,顯示此基因的表現量可能在口腔鱗狀上皮細胞移動能力上扮演重要角色。然而,對此基因的表現量如何影響細胞移動能力仍不清楚。為探討IFIT2基因是否藉由表皮間質轉化過程而改變了細胞移動能力,首先利用干擾核酸抑制口腔鱗狀上皮細胞中IFIT2基因,並觀察細胞是否出現表皮間質轉化過程的特性。 實驗結果顯示,在口腔鱗狀上皮細胞抑制IFIT2基因之mRNA核酸與蛋白質的表現會使得細胞出現類似間質細胞的細胞型態,而表皮細胞的標記蛋白質表現量明顯下降,間質細胞的標記蛋白質表現量增加,細胞的侵襲能力也有上升的趨勢。在文獻提出常見的調控表皮細胞的標記蛋白質轉錄調控因子中,於實驗結果發現當IFIT2表現減少,B-catenin及其下游 Twist 蛋白質除表現量增加之外,亦有進入細胞核的現象; Snail蛋白質表現量雖無顯著差異,但其亦可進入細胞核的現象。此外,抑制IFIT2基因會使NF-KB活化,並可能促使下游基因ZEB2表現量增加與進入細胞核。 綜合以上發現,於口腔鱗狀上皮細胞抑制IFIT2基因,可能會使得��-catenin與NF-�羠兩條訊息傳遞路徑活化,而進一步促使表皮間質轉化蛋白質使得表皮細胞的移動能力出現增加的趨勢。
Oral squamous cell carcinoma (OSCC), the most frequent malignant tumor of the oral cavity, is one of the major health-care dilemmas in the world. In Taiwan, the oral cancer mortality has been ranked at the 6th in the total cancer patient, but at the 4th place in male in 2008. Epithelial-mesenchymal transitions (EMT), a process whereby epithelial cell layers lose cell-cell contacts and undergo a dramatic remodeling of the cytoskeleton, is vital for morphogenesis. Interferon-induced protein with tetratricopeptide repearts 2 (IFIT2), was shown to be one of most responsive interferon stimulating genes (ISGs) to interferons and viruses, has shown an association between elevated IFIT2 expression and better prognosis in patients with OSCC and an inverse correlation between IFIT2 expression and cell migration. However, whether IFIT2 expression is associated with EMT of OSCC is unknown. In this study, si-IFIT2 oligonucleotide was to suppress E-cadherin but acquire vimentin expression. Meanwhile, EMT phenotype was observed and invasion ability was increased in cells knocking down IFIT2. Moreover, the protein levels of β-catenin and Twist were both increased in 48 hr and 72 hr. Nuclear translocation of β-catenin was found in si-IFIT2 group in 48 hr. Twist was also translocated into nucleus when IFIT2 was knockdown in 48 hr and 72 hr. Downregulation of IFIT2 significantly enhanced ZEB2 expression and nuclear translocation in 72 hr. Furthermore, si-IFIT2 transfection leaded to NF-�羠 activation both in 48 hr and 72 hr. Taken together, the present results suggest that IFIT2 expression is inversely associated with EMT and cell invasion ability which may mediate through activation of ��-catenin and NF-�羠 pathways.
Thesis Approval Form i
Acknowledgments vi
Chinese Abstract 1
Abstract 2
Introduction 3
Oral cancer 3
Oral carcinogenesis 6
Epithelial-mesenchymal transitions (EMT) 7
Molecular regulation of EMT 7
Interferon (IFNs) 12
Interferon-induced protein with tetratricopeptide repearts 2 (IFIT2) 14
Aims 15
Materials and Methods 16
Antibodies 16
Cell culture 16
RNA interference 16
Western blot analysis 17
RNA isolation 18
Reverse Transcription 18
Real-time PCR analysis 18
Immunohistochemical Staining 19
Transwell invasion assay 19
Immunoprecipitation 20
NF-κB activity assay 20
Statistical Method 21
Results 22
Downregulate IFIT2 induces changes of morphology and EMT markers 22
si-IFIT2 enhances the expression of b-catenin 23
si-IFIT2 enhances the Twist expression and nuclear translocation 24
Downregulation of IFIT2 induces Snail translocation 24
si-IFIT2 enhances the ZEB2/SIP1 expression and nuclear translocation 25
si-IFIT2 transfection leads to NF-kB activation 25
Discussion 27
References 33
Table 1. Ranking of Cancer mortality 39
Table 2. Primers for Real-time PCR analysis 40
Figures 41
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