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研究生:呂怡欣
研究生(外文):Yi-Hsin Lu
論文名稱:人類methionineadenosyltransferase1A基因受到甲狀腺素調控的研究
論文名稱(外文):Human methionine adenosyltransferase 1A is up-regulated by thyroid hormone
指導教授:林光輝林光輝引用關係
指導教授(外文):Kwang-Huei Lin
學位類別:碩士
校院名稱:長庚大學
系所名稱:基礎醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:中文
論文頁數:53
中文關鍵詞:甲狀腺甲狀腺素
外文關鍵詞:methionine adenosyltransferase 1Athyroid hormone
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甲狀腺素是一可調控細胞生長、發育、代謝與分化的重要因子。甲狀腺素藉由細胞核內的甲狀腺素受體將其訊號傳至細胞內調控下游基因。我們之前利用cDNA microarray分析技術研究在過度表現甲狀腺素受體的肝癌細胞株(HepG2-TRα1)中,甲狀腺素對下游基因的調控機制。在cDNA微列陣晶片上7600基因中,有201個基因受到甲狀腺素的正向調控,其中Methionine adenosyltansferase 1A(MAT1A)便是其中之一。Methionine adenosyltansferase(MAT)是生物體methionine代謝所必須的酵素之一,它與轉甲基反應(transmethylation reaction)、polyamine的合成以及肝癌細胞的增生有高度相關,而甲狀腺受體亦在抑制癌細胞中具有重要地位。因此探討此種重要分子受T3之調控機制及其生理意義是重要的課題之一。在過度表現甲狀腺素受體的肝癌細胞株中,MAT1A無論在mRNA或是蛋白質層次上皆受T3之正向調控,methionine adenosyltransferase活性亦受T3正向調控。加入轉譯抑制劑(Cycloheximide)會影響T3對MAT1A之調控,顯示其調控機制為甲狀腺素與其受體間接結合在MAT1A基因上游啟動子之甲狀腺素位元(Thyroid hormone responsive element,TRE)上,促使基因表現量上升。MAT1A基因在肝癌病人中表現較低。另外利用RNAi的方法剔除HepG2-TRα1細胞的MAT1A基因,其細胞移動能力明顯的上升;pro-MMP2、pro-MMP9及MMP-9活性亦增加;癌細胞轉移相關基因E-cadherin及β-catenin mRNA表現量亦有所改變。綜合以上結果我們推測,T3可能透過正向調控MAT1A而影響細胞的代謝;T3/TR可能在肝癌形成過程中扮演著tumor suppressor的角色。
Thyroid hormone (T3) regulates metabolism, growth, development, and differentiation. These activities are mediated by the nuclear thyroid hormone receptor (TRs). Previously, cDNA microarrays were performed; methionine adenosyltransferase 1A (MAT1A) was up-regulated by T3/TR. Methionine adenosyltransferase is an essential cellular enzyme which catalyses the formation of S-adenosylmethionine (SAM), the principal methyl donor and the precursor of polyamines. Here we investigated the biological significance of MAT1A regulation by T3 in HepG2 cell. MAT1A mRNA and protein expression were increased by T3 in HepG2-TR cells that over-expressing TR. Methionine adenosyltransferase activity was elevated after T3 treatment. The protein synthesis inhibitor, cycloheximide, inhibited the induction of MAT1A by T3, indicating that this regulation was indirect. MATⅠ/Ⅲ was silenced in hepatocellular carcinoma. Knock-down of MATIA expression raised cell migration and the activities of pro-MMP2, pro-MMP9 and MMP-9 in HepG2 cells. The mRNA expression of metastasis related genes (E-cadherin and β-catenin) were changed in MAT1A-knockdown stable clones. Together, this study demonstrates that MAT1A gene expression is indirectly up-regulated by T3. T3 may regulate cellular metabolism through up-regulated MAT1A. Furthermore, the regulation of T3/TR may play a suppressor role in hepatocarcinogenesis.
授權書...................................................................................................... iii
誌謝........................................................................................................... iv
中文摘要.................................................................................................... v
英文摘要................................................................................................... vi
目錄..........................................................................................................vii
前言……………………………………………………...….…………….1
甲狀腺素與其作用機制.....................................................................1
甲狀腺素受體………………………………………….……………1
甲狀腺荷爾蒙反應位元……………………………….……………2
甲狀腺素受體的變異與相關疾病…………………….……………3
Methionine adenosyltansferase(MAT)……………….....………..5
高甲硫胺酸血症(hypermethioninemia)……………....…………6
MAT活性轉譯後的調控………………………………..…………..6
MAT1A基因的調控……………………………..………………….7
MAT1A基因與肝癌的關係...............................................................8
材料與方法...............................................................................................10
細胞株...............................................................................................10
甲狀腺素(T3)的配製....................................................................10
T3 depleted (Td) serum 的配製........................................................11
RNA的萃取......................................................................................11
北方點墨法(Northern blotting)....................................................11
蛋白質萃取.......................................................................................13
蛋白質定量.......................................................................................13
西方點墨法(Western Blotting)....................................................14
Methionine adenosyltransferase酵素活性分析(MAT assay).....15
定量反轉錄聚合酶連鎖反應(Real-time quantitative-RT-PCR).15
建立穩定抑制MAT1A細胞株........................................................16
細胞遷移分析(Cell migration assay)...........................................16
Gelatin zymography..........................................................................17
統計方法...........................................................................................17
結果...........................................................................................................18
利用cDNA microarray技術分析T3對MAT1A之調控................18
T3促進MAT1A mRNA表現量上升................................................18
T3促進MATⅠ/Ⅲ蛋白質表現量上升............................................18
T3促進methionine adenosyltransferase酵素活性..........................19
T3對MAT1A之調控為間接作用...................................................19
MATⅠ/Ⅲ 蛋白質在肝癌病人中表現較低...................................20
肝癌細胞珠內生性MATⅠ/Ⅲ蛋白質表現情形............................20
建立穩定抑制MAT1A表現之細胞株............................................21
穩定抑制MAT1A細胞株表現低量MAT1A mRNA.....................21
穩定抑制MAT1A細胞株MAT活性較低......................................21
穩定抑制MAT1A表現量之細胞株細胞移動能力增加................22
穩定抑制MAT1A細胞株pro-MMP2、pro-MMP9及MMP9的活性增加...............................................................................................22
穩定抑制MAT1A細胞株E-cadherin及β-catenin mRNA表現量的改變...............................................................................................22
討論...........................................................................................................24
參考文獻...................................................................................................28
附錄...........................................................................................................37
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