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研究生:鄭仲益
研究生(外文):Cheng, Chung-Yi
論文名稱:探討LMX1A基因在肝癌中的功能及調控
論文名稱(外文):Study on the function and regulation of LMX1A in hepatocellular carcinoma
指導教授:林雅雯林雅雯引用關係
指導教授(外文):Lin, Ya-Wen
口試委員:施宇隆劉沁瑜
口試委員(外文):Shih, Yu-LuengLiu, Chin-Yu
口試日期:2012-06-15
學位類別:碩士
校院名稱:國防醫學院
系所名稱:微生物及免疫學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:81
中文關鍵詞:肝癌
外文關鍵詞:LMX1Ahepatocellular carcinomatumor suppressor gene
相關次數:
  • 被引用被引用:0
  • 點閱點閱:154
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  • 下載下載:3
  • 收藏至我的研究室書目清單書目收藏:0
肝細胞癌(HCC)是在世界上常見的惡性腫瘤之一。從我們先前的研究顯示,在子宮頸癌中LMX1A是透過DNA甲基化作用調控。也證明LMX1A在子宮頸癌體外和體內的腫瘤抑制功能。在本研究中欲探討,在肝細胞癌中LMX1A是否具有腫瘤抑制功能的作用及其基因的表現是否受到附基因體的調控。
為了研究在肝癌細胞中LMX1A是否扮演抑癌基因,我們在肝癌細胞中大量表現LMX1A,並檢查其對肝癌細胞的影響。LMX1A表現能顯著地抑制細胞群落形成能力,但對癌細胞的生長速率沒有明顯的影響。這些結果顯示,LMX1A在肝癌細胞中具有抑癌基因的功能。使用亞硫酸鹽定序(Bisulfite sequencing)和甲基化聚合酵素鏈鎖反應(MS-PCR)技術分析LMX1A啟動子區域甲基化的程度,結果發現在肝癌細胞HepG2中,LMX1A啟動子區域的甲基化程度是高的; PLC5和Tong是低的。利用反轉錄聚合酵素連鎖反應無法在這些肝癌細胞株中偵測到LMX1A基因的表現,而將PLC5細胞處理組蛋白去乙醯酶抑制劑(HDACi)TSA後,LMX1A mRNA表現有回復情形。由此結果可推測組蛋白修飾作用可能參與LMX1A基因表現的調控。
我們在LMX1A啟動子區域預測出幾個Sp1結合位點,且有文獻指出Sp1可能與組蛋白去乙醯酶1(HDAC1)作用,然後下調目標基因的啟動子活性。因此,我們進一步研究Sp1和HDAC是否參與LMX1A基因的調控。TSA處理過後的PLC5細胞,其LMX1A報導基因啟動子活性明顯增強。兩個位於LMX1A啟動區的Sp1結合位點發生突變時,LMX1A啟動子的活性明顯下降。此結果顯示,Sp1可能作為LMX1A的轉錄活化因子。我們也發現過度表現Sp1可以提高LMX1A啟動子活性。而當我們藉由Mithramycin(MTM, SP1抑制劑)抑制內源性Sp1後,再以TSA處理細胞,結果發現TSA未能增加LMX1A啟動子的活性。這個結果進一步證實了在肝癌細胞PLC5中Sp1可能扮演LMX1A轉錄活化因子的角色。此外,我們發現當PLC5細胞處理TSA後,組蛋白3上的離胺酸殘基14及組蛋白4有乙醯化現象。總結上述,由這些結果推測HDAC的和Sp1可能參與LMX1A調控當中,而當細胞處理TSA後,Sp1可能可作為LMX1A基因的轉錄活化因子。

Hepatocellular carcinoma (HCC) is one of the common malignant tumors in the world. Our previous work showed that LMX1A is downregulated through DNA methylation in cervical cancer. Furthermore, we characterized the tumor-suppressor function of LMX1A in cervical cancer in vitro and in vivo. Here, we would like to investigate whether LMX1A posses TSG function in HCC and is downregulated through epigenetic changes.
In order to study whether LMX1A plays as a tumor-suppressor gene in HCC, we overexpressed LMX1A in HCC cells and checked its effect on HCC cells. Ectopic expression of LMX1A could significantly inhibit colony formation. However, there is no significant decrease in cell proliferation by MTS assay. These data suggest that LMX1A posses TSG function in HCC cells. We used bisulifte sequencing and methylation-specific PCR (MS-PCR) to detect the promoter methylation status of LMX1A and found that HepG2 displayed promoter hypermethylation whereas the methyaltion status of PLC5 and Tong was low. RT-PCR analysis of these HCC cell lines showed transcriptional silencing. After PLC5 cells were treated with trichostatin A (TSA), histone deacetylase inhibitor (HDACi), LMX1A expression was restored. These data suggested that histone modification might be involved in the regulation of LMX1A.
There are several predicted Sp1 binding sites in the promoter region of LMX1A and some papers demonstrated that Sp1 may interact with histone deacetylase 1 (HDAC1), then down-regulate the promoter activity of target gene. Therefore, we want to further sutdy whether Sp1 and HDAC are involved in the regulation of LMX1A. LMX1A promoter luciferase activity was enhanced after PLC5 cells treated with TSA. After two Sp1 binding sites were mutated in LMX1A promoter, LMX1A promoter activity was decreased. It implied that Sp1 might play as a transactivator of LMX1A. Then we found Sp1 could enhance LMX1A promoter activity by overexpression of Sp1. Moreover, when we knocked down endogenous Sp1 by Mithramycin(MTM, Sp1 inhibitor), LMX1A promoter activity was failed to elevate after cells treated with TSA. This result further proved Sp1 might play as a transactivator of LMX1A in PLC5 cell. Furthermore, we found the lysine 14 of histone 3 and histone 4 were acetylated after PLC5 cells treated with TSA. Taken together, these data suggest that HDAC and Sp1 might be involved in the regulation of LMX1A, and after cells treated with TSA, Sp1 might play as a transactivator of LMX1A.


第一章 緒論 (Introduction) .................................................................1
第一節、肝癌的形成及致病機轉 .........................................................1
第二節、附基因改變與癌症相關性..........................................................1
第三節、LMX1A(LIM homeobox transcription factor 1 ,alpha)蛋白質.......................4
壹、LIM 家族簡介.................................................................4
貳、LMX1A的功能與癌症相關之研究....................................................5
第四節、轉錄因子Sp1 (Sp1 transcription factor).........................................6
壹、Sp1簡介......................................................................6
貳、Sp1與癌症....................................................................8
參、Sp1於附基因體調控機制中所扮演之雙重角色..........................................9
第五節、研究起源......................................................................10

第二章 材料與方法 (Materials & Methods).....................................................13
第一節、LMX1A在肝癌扮演抑癌角色........................................................13
壹、細胞培養(Cell culture).....................................................13
貳、轉染作用(Transfection)與LMX1A細胞株之篩選....................................13
參、萃取總蛋白質(Total protein).................................................14
肆、蛋白質濃度之測定..............................................................15
伍、蛋白質膠體電泳(SDS-PAGE)......................................................15
陸、西方墨點法(Western blot)....................................................16
染、細胞癌化程度分析(Tumorigenicity assays).......................................18
第二節、LMX1A 啟動子上甲基化程度之測試...................................................20
壹、DNA的萃取與定量...............................................................20
貳、亞硫酸氫鈉(Sodium Bisulfite)處理.............................................21
參、甲基化聚合酵素鏈鎖反應(Methylation specific PCR, MSP)..........................22
肆、亞硫酸鹽定序(Bisulfite sequencing)..........................................23
第三節、在不同處理細胞中LMX1A的表現量....................................................27
壹、去乙烯蛋白抑制劑Trichostatin A (TSA)的處理.....................................27
貳、細胞全核醣核酸 (Total RNA)的萃取...............................................27
參、互補去氧核醣核酸(cDNA)之置備 .................................................28
肆、反轉錄聚合酵素連鎖反應(Reverse Transcription Polymerase Chain Reaction, RT-PCR)....29
伍、定量聚合酶連鎖反應(Quantitative Polymerase chain Reaction, Q-PCR)............30
第四節、LMX1A之啟動子在肝癌細胞中基因表現分析.............................................31
壹、細胞培養(Cell culture).......................................................31
貳、轉染作用 (Transfection).......................................................31
叁、報導基因表現分析 ( Luciferase reporter assay)..................................32
第五節、LMX1A之啟動子在肝癌細胞中與Sp1的影響..............................................33
壹、細胞培養(Cell culture).......................................................33
貳、轉染作用 (Transfection).......................................................33
叁、報導基因表現分析 ( Luciferase reporter assay)..................................34
肆、下調Sp1對LMX1A啟動子活性的影響..................................................35
伍、統計方法分析 ...................................................................35

第三章 結果 (Results).........................................................................36
第一節、LMX1A在肝癌細胞中的角色...........................................................36
壹、內源性LMX1A在肝癌細胞中之表現....................................................36
貳、外源性LMX1A抑制肝癌細胞癌化的能力................................................36
第二節、LMX1A基因表現與附基因體的調控有關..................................................37
壹、肝癌細胞株LMX1A啟動區甲基化之分析................................................37
貳、肝癌細胞株LMX1A基因表現之分析....................................................37
參、去乙醯化藥物Trichostatin A (TSA)對LMX1A表現之影響................................38
第三節、組蛋白去乙醯酶(HDAC)、轉錄因子Sp1與LMX1A基因調控機制之關聯...........................38
壹、研究起源.......................................................................38
貳、HDAC對LMX1A啟動子活性的影響.....................................................39
參、突變Sp1轉錄因子結合區對LMX1A啟動子活性的影響......................................40
肆、外源性Sp1對LMX1A啟動子活性的影響.................................................42
伍、抑制Sp1對LMX1A啟動子活性的影響...................................................43
陸、去乙醯化藥物Trichostatin A (TSA)對組蛋白乙醯化之影響..............................44

第四章 討論 (Discussion)......................................................................45
第一節、轉錄因子Sp1對LMX1A之調控機制......................................................45
第二節、組蛋白修飾作用對LMX1A報導基因載體之調控.............................................47

第五章 結論 (Conclusion)......................................................................49
第六章 參考文獻 (References)...................................................................51


圖目錄
圖1 肝癌細胞株中LMX1A基因表現分析................................................................57
圖2 於肝癌細胞株內建立穩定表現LMX1A的細胞株.......................................................58
圖3 外源性LMA1A對肝癌細胞株HepG2/PLC5生長速率的影響...............................................60
圖4 (A)(B) LMA1A對肝癌細胞群落形成之影響.........................................................61
圖5 ..........................................................................................62
(A) 以甲基化聚合酵素鏈鎖反應偵測肝癌細胞中LMX1A啟動子之甲基化程度..................................62
(B) 以亞硫酸鹽定序確認肝癌細胞株內LMX1A啟動子之甲基化程度.........................................63
圖6 肝癌細胞中Trichostatin A對LMX1A基因表現的影響.................................................64
圖7 以報導基因活性測試各啟動子片段之LMX1A啟動子活性.................................................66
圖8 Trichostatin A對LMX1A啟動子活性的影響........................................................67
圖9 比較野生株與突變Sp1轉錄因子結合區之LMX1A啟動子的活性測試.........................................68
圖10 Trichostatin A對野生株與突變Sp1轉錄因子結合區之LMX1A啟動子的活性測試............................69
圖11 以報導基因活性測試偵測外送轉錄因子Sp1對LMX1A啟動子活性之影響.....................................70
圖12 選擇適當Mithramycin濃度對轉錄因子Sp1、報導基因活性及肝癌細胞之影響...............................72
圖13 以報導基因活性測試偵測下調轉錄因子Sp1對LMX1A啟動子活性之影響.....................................74
圖14 Trichostatin A對組蛋白乙醯化之影響...........................................................76

表目錄
表1 本研究中所使用之引子對..................................77

附圖目錄
附圖1 民國98年六月衛生署所公布癌症死因比較圖..................78
附圖2 LMX1A與其家族蛋白LIM之蛋白質結構......................79
附圖3 Sp1與其家族蛋白Sp3之蛋白質結構........................80
附圖4 LMX1A表現載體 (pcDNA3.1-LMX1A-V5)...................81
附圖5 對照組載體pcDNA3.1-HisA.............................81


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