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研究生:蔡孟妙
研究生(外文):Meng-Miao Tsai
論文名稱:miR-31於口腔鱗狀上皮細胞癌中經由調控FIH表現而活化HIF訊息路徑
論文名稱(外文):miR-31 Ablates Expression of the HIF Regulatory Factor FIH to Activate the HIF Pathway in Oral Squamous Cell Carcinoma
指導教授:林姝君林姝君引用關係
指導教授(外文):Shu-Chun Lin
學位類別:博士
校院名稱:國立陽明大學
系所名稱:口腔生物研究所
學門:醫藥衛生學門
學類:牙醫學類
論文種類:學術論文
論文出版年:2011
畢業學年度:100
語文別:英文
論文頁數:97
中文關鍵詞:口腔鱗狀上皮細胞癌微小RNA
外文關鍵詞:oral squamous cell carcinomamiRNA
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口腔鱗狀上皮細胞癌在全世界皆是相當普遍的癌症。微小RNA是一種內生性的小分子RNA,對於細胞的生物功能具有重要的調節作用。本研究將針對在口腔鱗狀上皮細胞癌中異常表現的微小RNA進行研究。起初在腫瘤組織中篩選出三十一個表現異常的微小RNA,其中以miR-31在腫瘤組織以及細胞株中的表現量最高。在口腔鱗狀上皮細胞癌的細胞株中大量表現miR-31可以增加癌細胞在有氧環境下的生長、爬行以及在未貼附狀態下形成群落的能力,同時也促進腫瘤生成。在有氧環境下,FIH可藉由催化803天門冬氨酸的氫氧化而降低HIF-1α的活性,而miR-31被預測會結合至FIH的3'端非轉譯區域。在細胞株中大量表現miR-31可抑制內生性或外生性FIH的蛋白質表現量。可是一旦將miR-31在3'端非轉譯區域上的結合位突變之後,miR-31則無法再抑制FIH的表現。大量表現的miR-31可以經由抑制FIH表現,進而促進HIF-1α活性及下游基因VEGF表現。然而,FIH需要氧氣做為催化過程中的基質。因此當細胞處在缺氧環境時,miR-31就失去了促進細胞癌化的能力。FIH的大量表現可降低細胞的癌化能力,但若將其催化部位或雙體結合位突變,使失去活性的話,將會削減FIH的抑制癌化能力。依據腫瘤組織切片染色發現,miR-31的表現量與腫瘤細胞核中的FIH表現呈現反比;與原發性腫瘤相比,FIH的表現量在轉移的腫瘤組織中明顯降低。經由此研究得知,miR-31可以透過抑制FIH的表現,活化HIF-1α,進而增加口腔鱗狀上皮細胞癌的惡性程度。
Oral squamous cell carcinoma is a worldwide disease. MicroRNAs (miRNAs) are endogenously expressed non-coding RNAs important for biological and pathological functions. This study investigated the alterations of miRNA in OSCC. Initial screening identified 31 miRNAs disregulated in tumors. miR-31 was further confirmed as a markedly upregulated miRNA in microdissected tumor tissues and cell lines. Ectopic miR-31 expression significantly increased the abilities of proliferation, migration, anchorage-independent colony formation and tumorigenesis of OSCC cells. Factor-inhibiting HIF (FIH) inhibits the transcriptional activity of hypoxia-inducible factor-1α (HIF-1α) through hydroxylating the asparagine residue 803 (Asn803) in normoxia. miR-31 is predicted to target the 3’untranslated region (3’UTR) of FIH. Ectopic miR-31 repressed the levels of both endogenous and ectopic FIH. Mutation of the predictive miR-31 target site in FIH 3’UTR abrogated the repression of FIH driven by miR-31. Ectopic miR-31 increased the transactivation activity of HIF-1α and in turn upregulated the expression of vascular endothelial growth factor (VEGF) through repressing the level of FIH. However, the catalytic activity of FIH requires oxygen as substrate. The miR-31-associated oncogenic phenotypes were attenuated in hypoxia. Ectopic FIH suppressed tumorigenic phenotypes, which can be abrogated by mutation in catalytic domain and truncation of dimerization domain. The miR-31 expression was related to lower nuclear FIH in tumor tissues, and the decrease of FIH was found in metastatic OSCC lesions comparing to primary tumors. This study concludes that miR-31 is an oncomir for OSCC by increasing the HIF-associated phenotypes through targeting FIH.
List of Figures I
List of Tables II
List of Supplementary Figures III
List of Supplementary Tables IV
Abbreviations V
Abstract 1
中文摘要 2
Introduction 3
A. Oral Cancer 3
B. microRNAs (miRNAs) 4
C. Hypoxia and Cycling Hypoxia 7
D. Hypoxia-inducible Factor 1 (HIF-1) 10
E. Factor-inhibiting HIF-1 (FIH) 13
Thesis Aims 15
Material and Methods 16
A. Plasmids 16
B. Cell Works 19
C. Virus Works 22
D. Nucleic Acid Works 23
E. ProteinWorks 25
F. OSCC Tissues 28
G. Statistical and Bioinformatics Analysis 28
Results 29
Part A. High miR-31 expression in OSCC cells 29
Part B. miR-31 expression increased the oncogenic potential of OSCC cells 30
Part C. miR-31 targeted FIH and dowregulated its expression through directly binding to the 3’UTR 32
Part D. FIH expression decreased the oncogenic potential of OSCC cells in normoxia 35
Part E. miR-31 imposed oncogenic effects on OSCC cells through transactivating HIF activity 36
Part F. Downregulation of FIH and upregulation of VEGF during OSCC carcinogenesis 37
Discussion and Conclusion 39
Figures 45
Tables 67
Supplementary Figures 71
Supplementary Tables 77
References 79
Appendix 92


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