臺灣博碩士論文加值系統

Hispolon為桑黃分離出來的酚類化合物，已知可誘導癌細胞的凋亡與抗腫瘤作用。然而，在子宮頸癌中對於腫瘤的活性抑制以及所涉及之分子機制，至今還未有深入的探討。在本篇實驗中，我們發現Hispolon治療能抑制兩株子宮頸癌細胞的細胞轉移。在體外與體內實驗中，溶酶體組織蛋白酶S (Cathepsin S, CTSS)的下調對其腫瘤細胞轉移的抑制至關重要。此外，Hispolon誘發子宮頸癌細胞產生細胞自體吞噬，其增加LC3轉化和酸性囊泡胞器的形成。在機制方面，我們發現Hispolon透過細胞外訊號調節激酶 (Extracellular signal-regulated kinase, ERK)途徑抑制子宮頸細胞其細胞的移動能力，而阻斷ERK途徑則逆轉細胞自體吞噬所調節的細胞轉移與CTSS 的抑制。我們的研究結果表明，Hispolon所誘發的細胞自體吞噬對於降低CTSS活性來抑制子宮頸癌腫瘤轉移是至關重要的；這一發現為分子調控提供了新的視角。

Hispolon, a phenolic compound isolated from Phellinus igniarius, induces apoptosis and anti-tumor effects in cancers. However, the molecular mechanism involved in hispolon-mediated tumor-suppressing activities observed in cervical cancer is poorly characterized. Here, we demonstrated that treatment with hispolon inhibited cell metastasis in two cervical cancer cell lines. In addition, the downregulation of the lysosomal protease Cathepsin S (CTSS) was critical for hispolon-mediated suppression of tumor cell metastasis in both in vitro and in vivo models. Moreover, hispolon induced autophagy, which increased LC3 conversion and acidic vesicular organelle formation. Mechanistically, hispolon inhibited the cell motility of cervical cells through the extracellular signal regulated kinase (ERK) pathway, and blocking of the ERK pathway reversed autophagy-mediated cell motility and CTSS inhibition. Our results indicate that autophagy is essential for decreasing CTSS activity to inhibit tumor metastasis by hispolon treatment in cervical cancer; this finding provides a new perspective on molecular regulation.

第一章 中文摘要 4
第二章 英文摘要 5
第三章 縮寫表 (Abbreviation) 6
第四章 緒論 8
一 子宮頸癌 8
二 細胞自體吞噬 11
三 腫瘤轉移與半胱氨酸組織蛋白酶 15
四 Hispolon 之醫學研究 20
第五章 研究動機 22
第六章 實驗設計 23
一 以MTT Assay 分析Hispolon 對人類子宮頸癌細胞的影響 23
二 以Wound healing assay 與Chamber assay 分析Hispolon
對人類子宮頸癌細胞其細胞爬行能力之影響 23
三 經由Hispolon 處理於不同時間點下，利用西方墨點法
觀察pro-Cathepsin 與mature-Cathepsin 表現之變化，
以及利用Cathepsin S activity kit 分析Hispolon 對於
Cathepsin S 活性之影響 23
四 使用Cathepsin S siRNA 與Cathepsin S 過量表現證實
Cathepsin S 對於子宮頸癌細胞其轉移能力之影響 24
五 使用西方點墨法分析Hispolon 對細胞自體吞噬指標基
因LC3 蛋白質變化的影響 24
六 使用Acridine orange 染色分析Hispolon 對細胞中酸性
囊狀胞器 (Acidic vesicular organelles)表現量的影響 24
七 以GFP-LC3 轉染分析Hispolon 對細胞中細胞自噬小體的影響 25
八 透過GFP-LC3 蛋白變化以及溶酶體抑制劑Chloroquine 作用分析Hispolon 誘發的細胞自噬為阻斷態細胞自噬 (Block in flux) 或是細胞自噬流 (Normal flux) 25
九 利用LC3 siRNA 與Beclin 1 siRNA 以及溶酶體抑制劑
Chloroquine 作用分析細胞自體吞噬在Hispolon 抑制
細胞轉移中所扮演的角色 26
十 利用免疫螢光染色與免疫共沉澱分析Cathepsin S 有無與細胞自噬指標性蛋白LC3 以及泛素化蛋白Ubiquitin 相互結合 27

第七章 研究材料與研究方法 28
一 藥品試劑 28
二 實驗設備 30
三 試劑配製 31
四 實驗細胞株 (Cell lines) 33
五 細胞培養 (Cell culture) 34
六 細胞存活率測試 (Analysis of cell viability) 36
七 體外腫瘤轉移性試驗 (Tumor metastasis assay in vitro) 37
八 西方墨點法 (Western blot assay) 40
九 RNA 干擾實驗 (RNA interference experiments) 42
十 免疫沉澱法 (Co-Immunoprecipitation, Co-IP) 42
十一 酸性囊狀胞器分析 (Acidic vesicular organelles
observation)
43
十二 GFP-LC3 表現載體轉染與細胞自噬小體觀察 44
十三 免疫螢光染色 (Immuno Fluorescence Assay) 45
十四 測量組織蛋白酶S 之活性 46
十五 體內動物試驗 (In vivo tumor xenograft model) 46
十六 統計分析 (Statistical analysis) 47
第八章 結果 48
一 Hispolon 對於人類子宮頸癌細胞株之細胞存活率影響 48
二 Hispolon 抑制人類子宮頸癌細胞株其細胞爬行能力 48
三 Hispolon 對於人類子宮頸癌細胞株轉移中其蛋白水解酶之影響 48
四 Hispolon 抑制人類子宮頸癌細胞之pro-與mature-Cathepsin S 以及其活性 49
五 Cathepsin S 對於人類子宮頸癌細胞轉移之影響 50
六 Hispolon 促使人類子宮頸癌細胞產生細胞自體吞噬現象 (Autophagy) 51
七 Hispolon 促使人類子宮頸癌細胞產生酸性囊狀胞器
(Acidic vesicular organelle) 51
八 Hispolon 誘發子宮頸癌細胞產生細胞自噬小體
(Autophagosome) 52
九 Hispolon 誘發人類子宮頸癌細胞產生細胞自噬流(Normal flux) 52
十 Hispolon 經由誘發細胞吞噬來抑制子宮頸癌細胞之轉移 53
十一 Hispolon 透過細胞自體吞噬其溶酶體系統抑制人類子
宮頸癌細胞中Cathepsin S 之活性 53
十二 Hispolon 活化ERK 訊息傳遞路徑而抑制人類子宮頸癌細胞轉移 54
十三 Hispolon 透過ERK 訊息傳遞路徑誘發細胞自體吞噬並水解Cathepsin S 進而抑制人類子宮頸癌細胞的轉移 55
十四 Hispolon 抑制人類子宮頸癌SiHa 細胞株在老鼠體內
的轉移能力 56
十五 Hispolon 抑制人類子宮頸癌細胞轉移示意圖 57
第九章 討論 58
圖表目錄 62
第十章 圖表與圖表說明 64
第十一章 參考文獻 103

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