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系統識別號 U0026-2208201412352100
論文名稱(中文) 探討在肝癌中Sp1對於T細胞淋巴癌侵略和轉移基因2表現的作用機制
論文名稱(英文) Study the regulatory mechanism of Sp1 on T-cell lymphoma Invasion and Metastasis 2 (TIAM2) expression in Hepatocellular Carcinoma
校院名稱 成功大學
系所名稱(中) 分子醫學研究所
系所名稱(英) Institute of Molecular Medicine
學年度 102
學期 2
出版年 103
研究生(中文) 顏薇軒
研究生(英文) Wei-Hsuan Yen
學號 T16011024
學位類別 碩士
語文別 英文
論文頁數 45頁
口試委員 指導教授-孫孝芳
口試委員-蔡少正
口試委員-洪建中
中文關鍵字 肝癌  啟動子 
英文關鍵字 TIAM2S  Hepatocellular carcinoma  Sp1  promoter 
學科別分類
中文摘要 T細胞淋巴瘤的侵襲和轉移2(TIAM2)與T細胞淋巴瘤的侵襲和轉移1(TIAM1)為同源蛋白。TIAM1已被人們所知為鳥糞嘌呤核甘酸交換因子(Guanine nucleotide exchange factor, GEF) 且涉及許多不同類型惡性腫瘤。在我們先前的研究中顯示TIAM2S,為其中一TIAM2異構物,通常只表現在人腦中,但在肝癌 (Hepatocellular carcinoma, HCC) 中卻發現有異位表達的現象。雖然由臨床檢體、細胞及動物的實驗結果表明在肝癌腫瘤生成中 TIAM2S其功能為一致癌基因,然而對於TIAM2S其調節機制及病理功能仍是未知。利用分析工具預測TIAM2S 上游啟動子結合位,發現TIAM2S缺少TATA 且其上游啟動子具有GC-box (GGGGCGGGG)。Sp1為一轉錄因子可結合至富含GC的區段(motifs),廣泛的參與細胞生理以及多種腫瘤發生過程中。我們假設Sp1可結合至TIAM2S啟動子上並調節TIAM2S在肝癌細胞中的表達。本研究的目的為探討TIAM2S在肝癌中的異位表達是否藉由Sp1所介導。我們已進行凝膠遷移或電泳遷移率實驗 (Electrophoretic mobility shift assay, EMSA) 和染色質免疫沉澱技術 (Chromatin immunoprecipitation assay, ChIP),確認Sp1特異結合於TIAM2S啟動子區域。為了探討Sp1是否能夠調控TIAM2S基因的表現,我們進行TIAM2S啟動子活性分析實驗。TIAM2S核心啟動子確實在肝癌細胞中具活性且在Sp1過量表現下效果更顯著。此外,內生性TIAM2S與Sp1表現量密切相關。在不同肝癌細胞株內過量表達和抑制Sp1的表現量導致TIAM2S mRNA改變,由此可反映出Sp1能夠調控人類TIAM2S轉錄。最近研究顯示,當Sp1 於T379位點被磷酸化時可增加其轉錄活性且參與了腫瘤的發生。因此,我們也探討Sp1 於T379位點被磷酸化時是否會影響TIAM2在肝癌細胞中的表現。結果顯示,TIAM2S mRNA表現量是在野生型和T379突變型Sp1表現後之間沒有顯著性變化。另外在70% (42/60)的肝癌檢體中,Sp1表現量在腫瘤部分為增加且TIAM2S與Sp1的表現量具有正相關。在這項研究中,我們證明了Sp1正向調控TIAM2S的表現且此機制在肝細胞癌化中扮演重要角色。我們相信這個研究結果將助於開發新穎的治療肝癌的新方法。
英文摘要 T-cell lymphoma invasion and metastasis 2 (TIAM2) is the homologue of TIAM1, which is known as guanine nucleotide exchange factor (GEF). TIAM1 is associated with many types of malignancies. Our previous study showed that TIAM2S, one of the TIAM2 isoforms, is normally expressed only in the human brain but found aberrant expressed in hepatocellular carcinoma (HCC). Although results from clinical specimen, cellular and animal models showed that TIAM2S functions as an oncogene in the tumorigenesis of liver cancer, the regulatory mechanisms of TIAM2S and its pathological function remains largely unknown. TIAM2S was predicted as a TATA-less gene, which containing a GC-box (GGGGCGGGG) located in TIAM2S promoter region. Sp1 is a transcription factor that binds to GC-rich motifs and involved in a wide range of cellular processes as well as tumorigenesis in many types of cancers. We hypothesized that Sp1 may bind to TIAM2S promoter and regulate TIAM2S expression in HCC cells. The aim of this study is to examine whether ectopic expression of TIAM2S in liver cancer cells is mediated by Sp1. Here, we have performed EMSA and chromatin immunoprecipitation assay (ChIP) to confirm that Sp1 specifically binds to TIAM2S prompter region. To investigate whether Sp1 regulates TIAM2S gene expression, TIAM2S prompter assay were conducted. Indeed, TIAM2S core promoter was activated in HCC cell lines and the effect was more significant under Sp1 overexpression. Moreover, Endogenous TIAM2S expression correlates closely with levels of Sp1. Overexpression and knockdown of Sp1 in different HCC cell lines resulted in changing the TIAM2S mRNA levels thus reflected that Sp1 specifically regulates human TIAM2S transcription. Recent studies showed that phosphorylation of Sp1 at T379 increase its transcriptional activity and is involved in tumorigenesis. Thus, we also examine whether phosphorylation of Sp1 at T379 affects TIAM2S expression in liver cancer cells. The results showed that TIAM2S mRNA level is not significantly changed between wild type and mutant T379 of Sp1 protein. Moreover, 70% (42/60) of HCC biopsies showed increases in the Sp1 level in the tumors and the pattern is correlated with TIAM2S. In this study, we have illustrated the important role of Sp1-mediated TIAM2S expression in HCC cells and it will help to develop new therapeutic strategy for the treatment of HCC.
論文目次 中文摘要.........................................................................................I
Abstract.......................................................................................III
誌謝.............................................................................................V
Table of contents..............................................................................VII
List of Figures.................................................................................IX
List of Tables...................................................................................X
1. Introduction..................................................................................1
1.1. T-Cell Lymphoma Invasion and Metastasis (TIAM) Family.......................................1
1.1.1. T-Cell Lymphoma Invasion and Metastasis-1 (TIAM1).........................................1
1.1.2. Mouse T cell lymphoma invasion and metastasis 2 (Tiam2, Stef).............................2
1.1.3. Human T-Cell Lymphoma Invasion and Metastasis-2 (TIAM2)...................................3
1.1.3.1. The Physiological Function and Regulation of TIAM2 in humans............................3
1.1.3.2. The Role of TIAM2 in tumorigenesis......................................................4
1.2. Transcription factor regulation of gene expression..........................................5
1.2.1. The transcription factor specificity protein 1 (Sp1)......................................6
1.2.2. The post-translational modifications of Sp1...............................................7
1.2.3. The Role of overexpression of Sp1 in tumorigenesis........................................8
1.3. Objective of this study.....................................................................9
2. Material and methods.........................................................................10
2.1. Cell lines.................................................................................10
2.2. Total, nuclear and cytosol proteins preparation............................................10
2.3. RNA Isolation and Quantitative RT-Real-time PCR............................................11
2.4. Western blot...............................................................................11
2.5. Midipreparation of plasmid DNA.............................................................12
2.6. TIAM2S promoter assay......................................................................12
2.7. Electrophoretic mobility shift assay (EMSA)................................................13
2.8. Chromatin Immunoprecipitation (ChIP).......................................................14
2.9. Adenovirus-expressing GFP-Sp1..............................................................15
2.10. shRNA knockdown...........................................................................15
2.11. Post-translational modification assay.....................................................15
2.12. Statistical analysis......................................................................16
3. Results......................................................................................17
3.1. Sp1 specifically binds to TIAM2S promoter region...........................................17
3.2. Expression of TISM2S is correlated with the level of Sp1 in various HCC cell lines.........17
3.3. Sp1 positively regulates human TIAM2S mRNA expression......................................18
3.4. Expression pattern of TIAM2S in clinical HCC samples was associated with Sp1 expression....20
4. Discussions..................................................................................21
4.1. TIAM2S promoter can be activated upon Sp1 expression.......................................21
4.2. Sp1 positively regulates TIAM2S transcription..............................................21
4.3. Other possible mechanisms to regulate TIAM2S gene expression...............................22
4.4. Conclusion.................................................................................22
5. Figures......................................................................................24
6. Tables.......................................................................................35
7. References...................................................................................37
8. Appendixes...................................................................................45
Appendix 1. Gene structure of TIAM family.......................................................45
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