臺灣博碩士論文加值系統

中文摘要
肺癌高居國人十大癌症死因的第一位，而癌細胞的轉移是導致肺癌死亡率與預後結果不佳的主因。因此了解轉移過程中分子間訊息傳遞的機制，並找出有潛力可作為肺癌轉移的生物指標，可能可改善肺癌治療的困境。有研究指出肺癌病患體內若有岩藻醣轉移酶 4 (Fucosyltransferase 4, FUT4) 的過量表現會有較差的五年存活率。實驗將基因轉殖入人類肺腺癌細胞株 A549 內後發現 A549 細胞內熱休克蛋白 27 (Heat shock protein 27, HSP27) 表現量增加。HSP27 為一種助疊蛋白，在癌細胞內參予許多細胞間的生化反應。HSP 27 在癌細胞內的高表現影響細胞的生長、對治療產生抗性甚至影響癌細胞的轉移行為。我們實驗結果顯示 HSP27高表現量的 A549-fut4 細胞，有較佳的生長率。利用 Wound healing assay 與 Transwell assay 顯示 A549-fut4 細胞移動能力較差。使用 Matrigel-transwell assay 觀察兩株細胞的侵入能力，發現 A549-fut4 細胞表現出較優異的侵入能力。A549-fut4細胞內 MMP2 與 MMP9 mRNA 表現量高於 A549-mock。為探討 HSP27 在轉移時所扮演的角色，實驗使用 RNAi 技術抑制 HSP27 於 A549-fut4 細胞內的表現。實驗結果顯示減少 HSP27 於 A549-fut4 內的表現可降低其移動與侵入能力。實驗顯示抑制 HSP27 於 A549-fut4細胞內的表現後，MMP2 與 MMP9 mRNA也隨之下降。這些實驗結果顯示，HSP27 可能具有調控肺腺癌細胞轉移的潛力，因此減少 HSP27 於肺腺癌細胞表現，可能會減緩肺腺癌轉移行為。

Lung cancer is the leading cause of mortality in Taiwan. Metastasis to secondary sites remains the major cause of lung cancer associated death. Hence, more clearly understand the molecular mechanisms underlying the metastasis process and to develop novel potential biomarker for lung cancer could improve therapeutic treatments. High expression level of fucosyltransferase 4 (FUT4) in lung cancer patients showed low 5-year survival rate. Heat shock protein 27 (HSP27) was significantly elevated in FUT4 transfected A549 (A549-fut4) cells. HSP27 is a molecular chaperone in cellular response for variety of stresses. Studies showed that HSP 27 have various cellular functions to promote differentiation, proliferation, motility and metastasis in cancer cells. Our results revealed high induced HSP 27 in A549-fut4 cells have worse migration ability by Wound healing assay and Transwell assay. Used Matrigel-transwell assay to observe invasion ability showed that A549-fut4 has better invasion ability. A549-fut4 has higher MMP2 and MMP9 mRNA expression than A549-mock. We further used RNAi technique to analyze the role of HSP27 in migration and invasion abilities. After HSP27 knock-down, migration and invasion abilities of A549-fut4 were greatly reduced. Furthermore, we observed MMP2 and MMP9 mRNA expression, we found MMP2 and MMP9 mRNA with lower expression after HSP27 knock-down. Accordingly, HSP27 has potential to modulate lung cancer cell-related process. Therefore, knock-down the expression level of HSP27 in lung cancer cells may decrease its metastastic power.

中文摘要 VI
Abstract VII
壹、 前言 1
貳、 文獻整理 3
一、 肺癌 3
(一) 罹患肺癌的危險因子 4
(二) 肺癌治療 4
二、 醣基 (Glycan) 5
(一) 單醣與醣基 5
(二) 醣蛋白 6
(三) 醣基與癌症 6
三、 岩藻醣轉移酶 (Fucosyltransferase) 8
(一) 鳥糞嘌呤二磷酸岩藻醣生合成 (Guanosine-diphosphate fucose, GDP-Fuc) 8
(二) 岩藻醣轉移酶的結構 9
(三) 岩藻醣轉移酶的種類 9
四、 熱休克蛋白 27 (Heat shock protein 27) 11
參、 材料與方法 14
一、 實驗材料 14
(一) 細胞培養 14
(二) 蛋白質萃取及定量 14
(三) 西方點墨法 14
(四) 細胞生長率與存活率 15
(五) RNA 萃取 16
(六) 反轉錄與即時轉錄聚合酶連鎖反應 (RT-qPCR) 16
(七) 基因默化 16
(八) 細胞侵入能力分析 16
(九) 細胞移動能力分析 (Transwell assay) 17
(十) 細胞移動能力分析 (Wound healing assay) 17
二、 實驗方法 17
(一) 細胞培養 17
(二) 蛋白質萃取及定量 19
(三) 西方點墨法 20
(四) 細胞生長率與存活率 26
(五) RNA 萃取 27
(六) 反轉錄與即時轉錄聚合酶連鎖反應 (RT-qPCR) 28
(七) 基因默化 29
(八) 細胞侵入能力分析 30
(九) 細胞移動能力分析 (Transwell assay) 32
(十) 細胞移動能力分析 (Wound healing assay) 34
肆、 結果 35
(一) A549-fut4 與A549-mock 細胞生長率、移動能力和侵入能力比較 35
(二) 觀察HSP27 基因默化於 A549-fut4 細胞內的表現量對其移動能力和侵入能力之影響 37
伍、 討論 39
陸、 結論 43
柒、 參考文獻 44
捌、 圖 60
謝辭 78

圖目錄
圖一、利用西方點墨法偵測 HSP27 蛋白質於 A549-fut4 and A549-mock 兩株細胞內表現量。 60
圖二、使用即時聚合酶連鎖反應觀察 A549-fut4 and A549-mock 兩株細胞內 HSP27 mRNA 表現量的差異。 61
圖三、使用 WST-1 比較 A549-fut4 and A549-mock 兩株細胞於 24 與 48 小時細胞生長率。 62
圖四、利用傷口癒合試驗比較 A549-fut4 與 A549-mock 兩株細胞的移動能力。 63
圖五、利用 Transwell assay 比較 A549-fut4 與 A549-mock 兩株細胞移動能力。 65
圖六、利用 Matrigel-transwell assay 比較 A549-fut4 與 A549-mock 兩株細胞侵入能力。 67
圖七、使用即時聚合酶連鎖反應觀察 A549-fut4 and A549-mock 兩株細胞內 MMP2 和 MMP9 mRNA 表現量的差異。 69
圖八、利用西方點墨法偵測 siRNA 對A549-fut4 細胞內 HSP27 蛋白質表現量的抑制情形。 70
圖九、使用即時聚合酶連鎖反應觀察 siRNA 對 A549-fut4 細胞內 HSP27 mRNA 表現量的抑制情形。 71
圖十、使用 WST-1 觀察 siRNA 作用後對 A549-fut4 細胞存活率之影響。 72
圖十一、利用 Transwell assay 觀察 A549-fut4 在 siRNA 24-120 小時的作用下對其移動能力之影響。 73
圖十二、利用Matrigel-transwell assay 觀察 A549-fut4 在 siRNA 的作用下對其侵入能力之影響 75
圖十三、使用即時聚合酶連鎖反應觀察抑制 HSP27 對 A549-fut4 細胞內 MMP2 與 MMP9 mRNA 表現量的影響情形。 77

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