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研究生(外文):Hung-Liang Hsiao
論文名稱(外文):Analyzing the Promoter Activity of Thymosin β4 Gene and the Effect of Overexpressing Thymosin β4 on Apoptosis of SW480 Colon Cancer Cells
指導教授(外文):Yeu SuTe-Chang Lee
外文關鍵詞:thymosin β4gene expressioncolon cancer
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胸腺素 β4 (Thymosin β4, Tβ4) 最初由小牛胸腺分離出來的小分子蛋白質,其可藉由與單分子肌動蛋白 (G-actin) 結合來調節微纖維絲 (microfilament) 的聚合,而影響到細胞的移動與分裂。由於Tβ4在多種癌細胞中被發現有大量表現的現象,因此其被與癌症的發生有關。然而 Tβ4 基因的轉錄調控與致癌機制目前並不清楚。
本研究室先前的研究指出,小鼠胸腺素 β4 (mTβ4) 基因-278 到 +410的片段,能有效啟動報告基因在小鼠纖維母細胞(NIH3T3)中表現。 本研究則發現mTβ4基因的第一個表現子 (exon) 長度為56 bp,其轉錄起始點與大鼠及人類相似,轉錄起始點上游具有類似TATA box的區域,下游則有兩個啟動子下游元件 (downstream promoter element, DPE)。小鼠胸腺素 β4基因 -57到 +56 片段具有啟動子的活性, -118到 +56的活性是SV40啟動子的 8倍, -168到-119之間有核蛋白結合的抑制子 (silencer) 存在, -118到-89之間有促進子 (enhancer) 存在。小鼠胸腺素 β4基因啟動子在人類子宮頸癌(HeLa)與大腸癌(SW480)細胞也有相似的活性。
本研究室最近的研究顯示, 在Tβ4 大量表現的SW480大腸癌細胞中,Fas 的表現下降,其對 CH-11 (anti-Fas IgM) 的細胞毒性敏感度也較低。 本研究中想了解其他的細胞毒殺物質,在Tβ4 大量表現的大腸癌細胞中,引發凋亡 (apoptosis) 的機轉。 Tβ4 大量表現也能增加大腸癌細胞對表現 FasL之Jurkat T 淋巴癌細胞毒殺的抵抗力。進一步的研究顯示出,以基質金屬蛋白酶 (matrix metalloproteinases, MMPs) 抑制劑 GM6001處理細胞可以回復 Fas 的表現量,及增加對 CH-11 的敏感性。 Tβ4 大量表現可以增加大腸癌細胞對 doxorubicin 與 etoposide 之引發凋亡的抵抗力,但對於 5-FU 與 irinotecan 的毒殺作用則無影響。Tβ4 大量表現可以增加大腸癌細胞中 Survivin 的表現,並減少兩種 Topoisomerase II 抑制劑 (doxorubicin 和 etoposide) 活化 caspase-9 與 caspase-3。 本研究也發現,Survivin 呈陽性反應之第三期大腸癌病患有較差的存活率。 
本研究可做為深入探討 mTβ4 基因轉錄調控的基礎,以及了解 Tβ4 大量表現,如何使大腸癌細胞躲避免疫系統的監控與增加其抗藥性, 這些發現有助於未來開發治療大腸癌的新藥。
Thymosin β4 (Tβ4), a small peptide originally isolated from calf thymus, modulates the formation of F-actin microfilaments by sequestering the monomeric G-actin. Recent studies have shown that overexpression of the Tβ4 gene occurs in many human tumors. However, little is known about the regulation of Tβ4 gene expression and the effects of Tβ4 on tumor.
Our present study analyzed in details of the promoter of the mouse thymosin β4 (mTβ4) gene. This study found that the first exon of mTβ4 gene spans 56 bp with its cap site situated in a putative initiator highly similar to the consensus mammalian sequence. In addition, a TATA box-like motif and two consecutive downstream promoter elements were found and their locations are in agreement with the ones present in a variety of other genes. This study showed that the expression level of reporter gene driven by the -118 to +56 region of mTβ4 gene was approximately 8-fold higher than that directed by the SV40 promoter and significant promoter activity was found to be associated with the -57 to +56 fragment. A silencer that was bound by a nuclear protein was located in the region between the -168 to -119 and an enhancer whose effect did not seem to be dependent on protein binding was identified in the -118 to -89 region of this gene. Interestingly, neither of the regulatory sequences affected reporter expression directed by a heterologous viral promoter. Unexpectedly, the mTβ4 promoter functioned effectively in HeLa cervical carcinoma cells.
Since a downregulation of Fas in the Tβ4 overexpressing SW480 colon cancer cells and a reduction in their susceptibility to the cytotoxicity of an anti-Fas IgM (CH-11) have been demonstrated in our previous study. Effects of Tβ4 overexpressing on the apoptosis of SW480 cells induced by other cytotoxic agents were assessed. As expected, Tβ4 overexpressers were also more resistant to the toxic effect of the FasL-bearing Jurkat cells. However, pretreating these cells with an MMP inhibitor not only increased Fas levels but also abolished their resistance to CH-11. Interestingly, even though the susceptibilities of the Tβ4 overexpressers to 5-FU and irinotecan remained the same, these cells were more resistant to doxorubicin and etoposide which triggered apoptosis via a mitochondrial pathway. Concordantly, activation of both caspase-9 and caspase-3 by the two aforementioned topoisomerase II inhibitors was diminished in the Tβ4 overexpressers accounted possibly by an increased expression of Survivin, an anti-apoptotic factor whose expression was upregulated by β-catenin. Finally, poor survival was found in stage III colon cancer patients whose tumors were stained positively by the anti-Survivin antibody.
Taken together, this study provide crucial information for further elucidation of the transcriptional regulation of mTβ4 gene as well as for designing a better approach for colon cancer treatment by targeting Tβ4 expression.
第一章、 緒論6
一、 研究目標7
二、 背景介紹7
3、胸腺素β 與大腸癌的關係10
三、 實驗設計12
第二章、 研究材料與方法13
一、 細胞培養14
二、 質體構築14
三、 細胞轉染16
四、 報告基因活性分17
五、 引子延伸 (primer extension) 17
六、 生物資訊分析19
七、 膠體電泳位移分析 (EMSA) 20
八、 細胞存活分析 (MTT assay) 21
九、 西方墨點法 (Western blotting) 21
十、 流式細胞儀分析23
十一、 反轉錄-聚合酶鏈鎖反應 (RT-PCR) 23
十二、 Caspase 活性分析25
十三、 免疫化學組織染色25
十四、 統計方法25
第三章、 小鼠胸腺素β4基因啟動子活性的分析26
一、 前言27
二、 實驗過程28
三、 研究結果28
四、 討論31
第四章、 胸腺素β4基因大量表現對免疫細胞
一、 前言41
二、 實驗過程42
三、 研究結果43
四、 討論46
第五章、 綜合討論與未來展望61
一、 綜合討論62
二、 未來展望65
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