臺灣博碩士論文加值系統

TGF-beta-induced factor homeobox 2（TGIF2）基因位於第20對染色體20q11.2-q12位置，在先前研究發現，TGIF2會經由招募histone deacetylases和經由TGIF binding site在TGF-β路徑產生抑制轉錄作用，且有文獻指出在卵巢癌中發現TGIF2基因有大量表現情形。但TGIF2基因在肺癌的角色目前尚未有研究指出，所以本實驗室利用real-time PCR檢測肺癌病人組織TGIF2表現量，發現正常組織表現量高於腫瘤組織，且在肺癌細胞生長試驗、群落形成、細胞轉型試驗及細胞週期變化中，我們發現當使用HA-TGIF2載體促使TGIF2表現時會降低細胞生長。且依據轉型生長試驗，抑制TGIF2會增強細胞的轉型能力且促進TGIF2表現則會使轉型能力變差。而TGIF2會藉由細胞凋亡及調控細胞G1期以控制細胞生長速度，且TGIF2過度表現細胞會誘導細胞凋亡且降低在G1期的比例。在轉移試驗中，我們發現TGIF2可增加轉移能力而且使細胞型態改變。接著進行細胞侵潤試驗，發現當TGIF2過度表現時侵潤能力上升，但在CH27干擾抑制TGIF2者則無影響。並且我們發現TGIF2可能經由抑制JNK路徑來調控生長。最後我們利用動物模式觀察到過度表現TGIF2會抑制腫瘤的生長能力。綜合以上結果，TGIF2在部份肺癌細胞株中可能扮演了降低細胞增生及細胞轉型能力，但此現象並不存在於轉移及侵潤試驗。

TGF-beta-induced factor homeobox 2 (TGIF2) gene lies in the chromosome 20q11.2-q12 position. TGIF2 will recruit histone deacetylases and repress TGF-β-induced transcription via TGIF binding site. It has been reported TGIF2 gene has high expression level observed in ovarian cancers. The role of TGIF2 in lung cancer tumorigenesis is unknown. Our laboratory used real-time PCR to measure the TGIF2 gene expression level in lung cancer patient tissues, and that mRNA level of TGIF2 gene in normal tissues is higher than tumor tissues. In this study, we did the following experiments: cell growth assay, colony formation, anchorage-independent growth assay, cell cycle distribution and animal experiment. We found out when we used HA-TGIF2 vector to promote TGIF2 expression, it would decrease cell growth. According to anchorage-independent growth assay, reduced TGIF2 expression has better effect in cell transformation and enhanced TGIF2 expression has worse effect in cell transformation. And TGIF2 overexpressed cells will induce apoptosis and decrease the percentage in G1 phase. In the experiments of metastasis, we found that TGIF2 could increase migration and change cell shape. In invasion assay, TGIF2 overexpressed cells could increase invasive ability but TGIF2 knockdown cells doesn’t have such effect. Also, TGIF2 gene may modulate JNK pathway to affect lung cancer cell growth. In animal model, the decreased ability of tumor growth was observed in TGIF2 overexpressed cells. In conclusion, TGIF2 may play a role in reducing cell proliferation, cell transformation but not in metastasis and invasion in some lung cancer cell lines studied here.

壹、 中文摘要 5
貳、 英文摘要 6
參、 前言
一、肺癌流行病學及危險因子 7
二、肺癌的分類及成因 8
三、鑑定參與肺癌形成基因--人類TGF-β-induced factor homeobox 2基因 9
四、肺癌與化學療法 10
五、癌細胞的轉移 10
六、MAPK的簡介 11
七、Akt的簡介 13
八、細胞週期調控蛋白 13
肆、 研究動機 16
伍、 實驗材料
1、藥品 17
2、抗體 17
3、酵素 18
4、細胞株來源 18
5、基因載體來源 18
6、其他 18
陸、 實驗方法
1. 細胞培養 (cell culture) 19
2. shRNA TGIF2干擾載體（vector）的構築 20
3. HA-TGIF2過度表現載體的構築 22
4. 微量質體DNA的萃取 24
5. 轉染作用 (transfection) 24
6. Stable clone的篩選(selection)步驟 25
7. 西方墨點法 (Western blot) 25
8. 細胞計數生長試驗 27
9. 3-(4, 5-dimethylthiazol-2-yl)-25-diphenyltetrazolium bromide分析法(MTT生長試驗) 27
10. 群落形成試驗 (colony formation) 28
11. 軟培養基非附著性細胞生長試驗
（anchorage-independent growth assay） 28
12. Propidium iodide染色法 29
13. 細胞轉移侵潤試驗（modified Boyden chamber） 29
14. 定量PCR (real time PCR) 31
15. 動物模式--腫瘤皮下注射 31
16. 統計分析 31
柒、 實驗結果
一、利用real time PCR定量TGIF2基因在正常肺臟組織與肺癌組織
中的差異表現量 33
二、觀察人類肺癌細胞株內生性TGIF2之表現 33
三、構築shTGIF2干擾載體及TGIF2過度表現載體 34
四、利用轉染shRNA TGIF2及HA-TGIF2改變人類肺癌細胞株內生
性TGIF2之表現 35
五、觀察TGIF2的表現對於人類肺癌細胞株生長能力的影響 35
六、觀察TGIF2基因表現對於人類肺癌細胞株群落形成的影響 36
七、觀察TGIF2基因表現對於人類肺癌細胞轉型的影響 36
八、觀察TGIF2的表現對於人類肺癌細胞株的細胞週期及細胞凋亡
的影響 37
九、觀察TGIF2的表現對於人類肺癌細胞之細胞週期調控蛋白的影
響 38

十、觀察TGIF2的表現對於人類肺癌細胞株內生性MAPKs與Akt之活化影響 38
十一、觀察TGIF2的表現對於人類肺癌細胞株的移行能力及侵潤能
力的影響 39
十二、觀察TGIF2的表現在動物模式上的腫瘤生長情形 40
捌、 討論 42
玖、 圖表說明
圖一、觀察在肺癌病人之正常及腫瘤組織中TGIF2基因表現量差異 48
圖二、觀察人類肺癌細胞株、正常肺臟細胞株及人類乳癌細胞株內
生性TGIF2表現量 49
圖三、shRNA TGIF2干擾載體的構築 50
圖四、利用轉染技術改變人類肺癌細胞株內生性TGIF2之表現 51
圖五、利用細胞計數觀察TGIF2的表現對於肺癌細胞生長的影響 52
圖六、利用MTT assay觀察TGIF2基因的表現對於肺癌細胞生長的
影響 53
圖七、利用細胞群落形成試驗觀察TGIF2表現對於肺癌細胞群落形
成的影響 54
圖八、利用anchorage-independent growth assay觀察轉染HA-TGIF2
對於H460細胞轉型能力的影響 56
圖九、利用anchorage-independent growth assay觀察轉染shRNA
TGIF2對於CH27細胞轉型能力的影響 57
圖十、分析轉染HA-TGIF2對H460細胞株之細胞週期的影響 58
圖十一、分析轉染shRNA TGIF2對CH27細胞株之細胞週期的影響 59
圖十二、觀察TGIF2的表現對於H460細胞之細胞週期調控蛋白的
影響 60
圖十三、觀察抑制TGIF2的表現對於CH27細胞之細胞週期調控蛋
白的影響 62
圖十四、觀察TGIF2的表現對於人類肺癌細胞株內生性MAPKs之
活化的影響 64
圖十五、觀察TGIF2的表現對於人類肺癌細胞株內生性Akt之活化
的影響 66
圖十六、觀察TGIF2基因對於人類肺癌細胞株型態的影響 67
圖十七、觀察轉染HA-TGIF2對於H460細胞株移行能力的影響 68
圖十八、觀察轉染shRNA TGIF2對於CH27細胞株移行能力的影響 69
圖十九、觀察轉染HA-TGIF2對於H460細胞株侵潤能力的影響 70
圖二十、觀察轉染shRNA TGIF2對於CH27細胞株侵潤能力的影響 71
圖二十一、利用動物模式觀察TGIF2的表現對於腫瘤生長的影響 72
拾、 附圖
附圖一、全國死因及癌症死亡率趨勢圖(行政院衛生署2007年) 74
附圖二、細胞週期參考圖 75
附圖三、TGIF2過度表現載體 76
附圖四、實驗結果流程圖 77
附圖五、MAPK pathways 78
附圖六、實驗動物腫瘤內TGIF2蛋白表現量 79
拾壹、 附表
附表一、HA-TGIF2質體設計序列表 80
附表二、引子序列表 81
附表三、觀察在不同肺癌病人之正常及腫瘤組織中TGIF2基因的相
對表現量 82
拾貳、 參考文獻 83

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