臺灣博碩士論文加值系統

根據衛生署癌症登記報告結果指出，口腔癌在台灣男性十大癌症死亡率為第三位。除此之外，口腔癌發生的年增率也有逐年上升的趨勢，是台灣地區癌症發生年增率最高的癌症。光動力治療（photodynamic therapy，PDT）是新興的癌症治療方式，5-胺基酮戊酸光動力治療（5-aminolevulinic acid，ALA） 為新研發的第二代光感藥物（photosensitizer）。 先前我們對口腔癌病變所進行的臨床試驗結果，證實ALA的光動力治療，具有用於口腔癌病變治療的潛力，但ALA光動力治療亦可誘導環氧化酵素-2 (Cyclooxygenase-2, COX-2)的產生，而其作用機轉至今尚未明瞭。 由於COX-2 本身可透過血管生成，細胞增殖及轉移等方式，來促進口腔癌細胞的擴展。 本研究以人類口腔癌細胞株Ca9-22探討ALA光動力治療誘導COX-2產生的可能機制， 以期能藉由瞭解ALA的光動力治療誘導COX-2表現上升的路徑，進而提升光動力治療在臨床疾病治療上的功效。 我們發現， Ca9-22細胞株經ALA光動力治療後，COX-2的蛋白質在刺激後3小時開始上升，6小時達到高峰，9小時之後開始下降，48小時後便降回正常值，而且mRNA的表現也在20分鐘後開始上升，1小時達到高峰，9小時後降回正常值。 而ALA光動力治療可活化PI-PLC/PKCβ/NF-κB， 並發現它們參與ALA光動力治療誘發之COX-2表現。 以PI-PLC, PKC與NF-κB之抑制劑(分別為U-73122, Go6983與Bay 11-7082) 前處理可阻斷ALA光動力治療誘發之COX-2表現。 除了NF-κB外，ALA光動力治療亦增加Cyr61 的分泌，以Cyr61之 shRNA前處理可阻斷ALA光動力治療誘發之COX-2表現。 本論文首次指出ALA光動力治療可經由PI-PLC/PKCβ/NF-κB路徑調控COX-2之表現。 亦首次指出Cyr61在光動力治療誘發COX-2表現的路徑中扮演重要的角色。

Oral cancer is the fourth leading cause of cancer-related deaths in male population in Taiwan. Despite recent advances in radiotherapy and chemotherapy, the survival of patients with oral cancer has not improved significantly. Continued investigation of new chemotherapeutic agents is thus needed. Recently, 5-Aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) has been used to treat oral premalignant and malignant lesions with promising results in our clinical trials. However, previous studies showed that PDT induces the expression of proangiogenic factors, such as cyclooxygenase-2 (COX-2), thereby promoting cancer cell regrowth following PDT. In this study, we show ALA-PDT can also increase COX-2 expression. Pretreatment of Ca9-22 cells with specific inhibitors of Phosphatidylinositol-specific phospholipase C (PI-PLC; U-73122), protein kinase C (PKC; Go6983) and NF-κB (Bay 11-7082) inhibited COX-2 induction. In summary, ALA-PDT induces the COX-2 expression through the cascade of PI-PLC/PKCβ/NF-κB. Furthermore, we found ALA-PDT increased the expression of Cyr61. Pretreatment of cells with Cyr61 shRNA inhibited ALA-PDT induced COX-2 expression. To our knowledge, this is the first time to show PDT can induce Cyr61 expression and thereby promoting cancer cell regrowth following PDT.

目錄
口試委員會審定書…………………………………………………………………. I
誌謝…………………………………………………………………………………..II
中文摘要……………………………………………………………………………..III
Abstract………………………………………………………………………………V
第一章 緒論…………………………………………………………………………..1
1-1 口腔癌
1-2 口腔癌的治療
2-1 光動力治療
2-2 5-胺基酮戊酸光動力治療
2-3 ROS and cancer
3-1 環氧化酵素
3-2 COX-2 and Cancer
4-1 訊息傳遞
4-2 Protein kinase C
5-1 Phospholipase C
5-2 Phospholipase C in nucleus
6-1 Cysteine-rich 61
6-2 Cyr61 的功能與在癌症中所扮演的角色
7-1 Nuclear factor-kappa B
第二章 實驗材料與方法...........................................................................................17
2-1、細胞株培養
2-2、光動力治療
2-3、藥物處理
2-4、Transformation
2-5、質體抽取（plasmid extraction）
2-6、質體轉殖（plasmid transfection）
2-7、西方墨點法（Western blotting）
2-8、抗體的使用
2-9、RNA的萃取
2-10、反轉錄（Reverse transcription）
2-11、聚合酶連鎖反應（poly-chain polymerase）
2-12、免疫螢光染色
2-13、分離細胞核和細胞質
2-14、Electrophoretic-Mobility Shift Assay
2-15、Flow cytometry
第三章 研究動機……………………………………………………………………28
第四章 實驗結果……………………………………………………………………29
4-1、口腔癌細胞株Ca9-22在經過5-胺基酮戊酸光動力治療之後，細胞內環氧化酵素-2的蛋白質表現量明顯上升
4-2、ALA光動力治療誘導Ca9-22細胞內COX-2的mRNA表現量上升
4-3、在Ca9-22細胞內ALA光動力治療會誘導光感物質產生ROS
4-4、PKCβ參與ALA光動力治療所誘導Ca9-22細胞株中COX-2表現上升的訊息傳遞路徑
4-5、PI-PLC抑制劑U-73122，會抑制ALA光動力治療所誘導Ca9-22細胞株中COX-2表現上升
4-6、NF-κB參與ALA光動力治療所誘導Ca9-22細胞株中COX-2表現上升
4-7、Cyr61參與ALA光動力治療誘導COX-2表現量上升
第五章 討論................................................................................................................39
第六章 圖與表………………………………………………………………………45
第七章 參考文獻........................................................................................................60

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