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研究生:柯武賢
研究生(外文):Wu-SianKe
論文名稱:研究DNA甲基化在T細胞淋巴癌侵略和轉移基因2於肝癌細胞中異位性表現的機制
論文名稱(外文):Study the mechanism of ectopic expression of T-Cell Lymphoma Invasion and Metastasis 2 in Hepatocellular Carcinoma
指導教授:孫孝芳孫孝芳引用關係
指導教授(外文):Hsiao-Fang Sun
學位類別:碩士
校院名稱:國立成功大學
系所名稱:分子醫學研究所
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:2012
畢業學年度:100
語文別:中文
論文頁數:61
中文關鍵詞:肝癌細胞甲基化啟動子
外文關鍵詞:TIAM2SHCCmethylationCpGpromoter
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我們先前的研究證明,T細胞淋巴瘤的侵襲和轉移 2(TIAM2)是一個腫瘤相關的基因,可以促進上皮-間質轉化(EMT)因而導致細胞增生和侵襲。在成對的肝細胞癌(HCC)樣品中,我們發現TIAM2S在正常的肝細胞中是檢測不到的,但卻異位性表現於肝癌檢體。進一步的細胞及小鼠模式研究顯示,穩定的過量表達TIAM2S於非侵入性的肝癌細胞株中,可以促使其轉化為高侵襲性的癌細胞。總而言之,這些實驗結果說明TIAM2S是一個新穎的致癌基因,參與在肝癌的癌化機制,但是TIAM2S在肝癌細胞中異位表達的機制仍然未知。 DNA的甲基化是最被廣泛研究的表基因調控現象,不正常的甲基化影響了基因的表達,因而導致癌細胞中細胞生理上的急劇變化。基因組總體的低甲基化和局部的高甲基化已經在各類型的腫瘤研究中廣泛被報導,我們推測不正常的表基因調控導致了肝癌細胞中TIAM2S的異位性表達,因此本研究的目的主要針對DNA甲基化在肝癌細胞的異位表達TIAM2S機制進行探討。研究的具體目標是:一、透過生物資訊工具的分析,研究TIAM2S的5’端是否有可能調控基因表現的啟動子、轉錄因子或CpG島;二、分析TIAM2S 5’端的CpG島組成以及此CpG島對TIAM2S基因表現的影響;三、利用亞硫酸鹽處理細胞株的基因組DNA後,建立檢測TIAM2S內含子一的 CpG島甲基化程度的方法,並探討該位置甲基化的程度與TIAM2S表現量的關係;四、在成對的HCC臨床檢體中,分析TIAM2S內含子的 CpG島甲基化程度及與TIAM2S表現量的關係。本研究結果顯示,生物資訊分析預測TIAM2S轉錄起始點上游不具TATA box,但在-70bp~ -55bp的位置有GC box的結合序列,下游內含子一中則有一個CpG島。藉由構築包含不同TIAM2S上游區域的刪除質體並進行雙螢光酵素活性測試的結果顯示,TIAM2S上游地區具有啟動子的活性,其核心啟動區位於轉錄起始點上游的-87bp~ +82bp間,此外TIAM2S內含子一的CpG島的存在導致TIAM2S轉錄活性的下降。而DNA經由亞硫酸鹽的處理,並藉由之後的TA克隆和自動定序分析TIAM2S的CpG島的甲基化狀態。於肝癌細胞株中,HepG2的甲基化程度較高,PLC的甲基化程度較低,而PLC的TIAM2S表現量比HepG2來的高;除此之外,於60對成對的肝癌樣本中以及15個良性的肝血管瘤樣本中,全部60個正常組織和15個良性血管瘤的檢體都顯示高度的甲基化程度,而有20個肝癌病人的分析結果顯示,相較於其正常組織,腫瘤組織呈現低甲基化水平且其中的19個 (95%)顯示其TIAM2S的表達量是增加的。這些結果顯示TIAM2S內含子一的的CpG島的甲基化改變可能是促使TIAM2S在肝癌細胞中異位性表現的其中一項因素。但是在TIAM2S異位性表現的檢體中,只有38% (19/50)其甲基化的程度較低,這樣的結果也暗示了有其它未知的機制,參與在TIAM2S在肝癌細胞中的異位性表現機制。
Our previous study demonstrated T-cell Lymphoma Invasion and Metastasis 2 (TIAM2) is a tumor associated gene which promoted epithelial-mesenchymal transition (EMT) and resulted in cell proliferation and invasion. Using both cDNA panel and paired hepatocellular carcinoma (HCC) samples, we found that TIAM2S was undetectable in normal liver but ectopically expressed in HCC. Further studies demonstrated that stable overexpression of TIAM2S converted non-invasive human HCC cells into highly aggressive vascular tumors in cellular and mouse model. Together, these data suggest that TIAM2S is a novel oncogene and involves in the pathogenesis of HCC. Although the evidences are clear, the underlying mechanism of ectopic expression of TIAM2S in HCC is still unknown. DNA methylation is one of the most extensively studied epigenetic phenomenon, disturbances of methylation result in changes in gene expression, thus exerting drastic information onto biological behaviors of cancer. Both global hypomethylation and local hypermethylation have been reported in various types of tumors. We hypothesize that aberrantly epigenetic regulation causes ectopic expression of TIAM2S in cancer cells. The objective of this study is to illustrate the mechanism of TIAM2S ectopic expression in HCC. The specific aims of this study are to carry out reporter gene assay to identify the promoter region of TIAM2S, to study the role of CpG island in TIAM2S expression, to establish procedure for detecting methylation change on promoter and CpG island of TIAM2S, and to assay the methylation status of TIAM2S in paired clinical HCC samples. Variant deletion constructs including the promoter region of TIAM2S gene were generated and subjected for promoter activity analysis using dual-luciferase reporter assays. Our data revealed that TIAM2S upstream region possessed promoter activity and the core promoter region is located at the -87 bp upstream of the transcriptional start site to downstream +82 bp. In addition, the CpG island exhibited negatively regulated function to the expression of TIAM2S promoter. DNA was converted by bisulfite treatment and determined the methylation patterns following TA cloning and autosequencing. In HCC cell lines, the methylation level of HepG2 was higher than PLC but the TIAM2S expression level of HepG2 was lower than PLC, however, all normal parts of 60 HCCs and 15 benign Hemangioma revealed high methylation pattern. In addition, 18 HCCs revealed lower methylation level and 19 of them (95%) showed increasing-TIAM2S expression pattern. These results imply alternation of TIAM2S intron 1 CpG island methylation may involve in TIAM2S ectopic expression in HCC. However, only 19 HCCs (38%) showed hypomethylation level among 50 TIAM2S ectopic expression HCCs. The results imply that there are other unknown mechanisms involved in TIAM2S ectopic expression in HCC.
摘要 I
ABSTRACT III
誌謝 V
目錄 VII
圖目錄 IX
附錄目錄 X
英文縮寫對照表 XI
1. 緒論 1
1.1. T細胞淋巴侵略和轉移基因2 1
1.2. 啟動子與基因的轉錄作用 2
1.3. 遺傳 (GENETIC) 與表觀遺傳 (EPIGENETIC) 的調控 3
1.4. DNA的甲基化 4
1.5. 甲基化調控基因轉錄的機制 8
1.6. 研究動機、目的與特定目標 9
2. 材料與方法 10
2.1. 檢體與細胞株 10
2.2. 生物資訊工具 10
2.3. DNA的製備 (GENOMIC DNA PREPARATION) 11
2.4. 聚合酵素鏈鎖反應 (POLYMERASE CHAIN REACTION, PCR) 12
2.5. 建構不同的刪除型質體 (DELETION CONSTRUCT GENERATION) 12
2.6. 質體DNA的轉形作用 (PLASMID DNA TRANSFORMATION) 12
2.7. 質體DNA的製備 (PLASMID DNA PREPARATION) 13
2.8. 質體DNA短暫性的轉染作用 (PLASMID DNA TRANSIENT TRANSFECTION) 14
2.9. 雙螢光酵素活性分析 (DUAL-LUCIFERASE ASSAY) 14
2.10. 亞硫酸鹽轉換定序法 (BISULFITE-SEQUENCING PCR, BSP) 15
2.11. 總RNA的製備 (TOTAL RNA PREPARATION) 15
2.12. 反轉錄作用 (REVERSE TRANSCRIPTIONAL PCR, RT-PCR) 16
2.13. 即時定量聚合酶連鎖反應 (REAL TIME PCR, Q-PCR) 17
2.14. 甲基化敏感的限制酵素結合即時定量聚合酶連鎖反應 17
2.15. 統計分析 17
3. 結果 18
3.1. 生物資訊工具預測TIAM2S的5’端啟動子區域 18
3.2. TIAM2S的5’端具有啟動子的活性,且轉錄起始點上游-87BP~-43BP 的GC BOX與GATA-1可能扮演重要的角色 19
3.3. TIAM2S 內含子一的CPG 島對TIAM2S啟動子的轉錄具有調節的作用 19
3.4. TIAM2S 內含子一的CPG 島的甲基化可能與TIAM2S的表現有關 22
3.5. 肝癌病人的TIAM2S 內含子一的 CPG 島具有較低的甲基化現象度且具有較高的TIAM2S表現量 23
4. 結論與討論 25
5. 圖 30
6. 參考文獻 46
7. 附錄 55

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