根據美國癌症協會估計，肝癌在男性癌症死亡排名中位居第五，在女性癌症死亡排名中位居第八。而根據台灣衛福部統計，肝癌在台灣的癌症死亡排名中甚至連續幾年都排行第二名。肝癌的死亡率如此之高是由於肝臟神經在內部少有，所以癌症產生時不易察覺，察覺時也都到了中晚期，且肝癌的五年存活率非常低，增加了治療上的難度。因此在本研究中的主旨是希望能發現抑制肝癌的方法，並用蛋白質體學的方式來探討其抑制的機制。
牛樟芝 (Antrodia Cinnamomea)是一種真菌，原只生長於台灣的牛樟樹木中，在民間被當作解肝毒的一種食材，在學術研究上也被證實其成分之一的萜類化合物 (terpenoids)具有抑制肝癌細胞增生的能力。所以在實驗中首先以乙醇提取牛樟芝 (ethanolic extracts of Antrodia Cinnamomea, EEAC)，接著分別加入正常肝細胞株Chang Liver和肝癌細胞株C3A、HepG2中進行細胞存活率試驗 (MTT assay)。然後用蛋白質體學的方式去分析EEAC的效用，包括二維差異電泳 (2D-DIGE)、差異分析軟體DeCyder、介質輔助雷射脫附游離/飛行時間質譜 (MALDI-TOF-MS)找出差異之蛋白質。
透過SwissProt資料庫和KEGG路徑分析，將這些鑑定出來的蛋白質依據其功能與表現量進行分類，觀察到許多蛋白質在蛋白質摺疊、氧化還原調節、醣解作用的功能中表現量下降，因此我們推測EEAC會導致癌細胞產生內質網壓力 (ER stress)，進而誘導細胞凋亡。為了證實這個推測，我們進行了西方點墨法 (western blot)去壓跟內質網壓力相關的抗體，結果證實EEAC是透過蛋白質摺疊錯誤與細胞氧化還原不平衡所引起的內質網壓力來抑制癌細胞，導致細胞產生毒性而凋亡。

Of all the cancers discovered in patients living in Taiwan, liver cancer is the prevalent type of cancer diagnosed in patients. The American Cancer Society estimates liver cancer is the 5th leading cause of death in males and the 8th in females in the United States. Thus, our objective is to discover effective treatment options for liver cancer.
In this study, three cell lines are used, one normal liver cell lines, Chang Liver, and two hepatocellular carcinoma cell lines, C3A and HepG2. First, we perform MTT assays with ethanolic extracts of Antrodia Cinnamomea (EEAC), a Taiwan endemic fungus species used as an Asian folk medicine. Then, we use proteomic analysis including two-dimensional differential gel electrophoresis (2D-DIGE), DeCyder differential analysis software, matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) and immunoblotting to verify differentially expressed proteins. By searching SwissProt and KEGG pathway analysis, these identified proteins can be classified according to their subcellular locations, functional ontology, and expression profiles. In view of observing numerous proteins with their biological functions in protein folding, we performed immunoblotting to stain ER related antibodies specific to the target protein.
To sum up, our results indicated EEAC promote cytotoxicity in liver cancer cells rather than normal liver cells through ER-stress caused by protein misfolding and cellular redox unbalance.

致謝 4
縮寫清單 7
中文摘要 9
英文摘要 10
壹、 文獻探討 11
一、 肝癌 (Hepatic cancer, Liver cancer) 11
1. 肝癌之流行病學 11
2. 肝癌種類 13
3. 肝癌之危險因子 14
4. 肝癌之病徵 (圖 六) 15
5. 肝癌臨床分期 (表 一) 15
6. 肝癌篩檢方式 16
7. 臨床治療方式 16
二、 牛樟芝 (Antrodia cinnamomea, Antrodia camphorata) 17
1. 栽培技術 18
2. 牛樟芝成分 19
3. 牛樟芝之抗癌效用 20
三、 內質網壓力 (Endoplasmic reticulum stress, ER stress) 22
1. PERK路徑33 22
2. IRE1路徑34 22
3. ATF6路徑35 23
四、 蛋白質體學 (Proteomics) 25
1. 簡介 25
2. 蛋白質體學之重要性 26
3. 二維差異電泳 (Two-Dimensional Differential Gel Electrophoresis, 2D-DIGE) 27
4. 介質輔助雷射脫附游離/飛行時間質譜 (Matrix-Assisted Laser Desorption/ Ionization Time of Flight Mass Spectrometry, MALDI-TOF-MS) 31
貳、 研究目的 34
參、 材料與方法 35
一、 材料來源與藥品來源 35
1. 細胞株來源 (表 三) 35
2. 藥品與資料來源 (表 四) 35
二、 細胞株培養與繼代方法 36
三、 酒精萃取牛樟芝 (ethanolic extracts of Antrodia Cinnamomea, EEAC) 36
四、 細胞存活率試驗 (MTT assay) 36
五、 二維差異電泳 (Two-Dimensional Differential Gel Electrophoresis, 2D-DIGE) 37
1. 蛋白質樣品製備 37
2. 蛋白質螢光標定 37
3. 等電點聚焦電泳 (Isoelectric focusing, IEF) 38
4. 十二烷基硫酸鈉聚丙烯醯胺凝膠電泳 (Sodium dodecyl sulfate polyacrylamide gel electrophoresis, SDS-PAGE) 39
六、 影像分析 (DeCyder differential analysis software) 40
1. Image loader 40
2. Batch processor 40
3. 蛋白質點圈選 41
4. 統計分析 41
5. Coomassie blue染膠 42
七、 蛋白質身分鑑定 42
1. 膠內酵素水解蛋白質 (In-gel digestion) 42
2. 介質輔助雷射脫附游離/飛行時間質譜 (Matrix-Assisted Laser Desorption/ Ionization Time of Flight Mass Spectrometry, MALDI-TOF-MS) 43
3. 搜尋資料庫用以鑑定蛋白質身分 43
八、 蛋白質表現量之驗證 (Validation) 44
1. 蛋白質樣品配製 44
2. 西方點墨法 (Western blotting) 45
3. 內部標準品 (Internal control) 47
肆、 實驗結果 48
一、 用細胞存活率試驗 (MTT assay)測試藥物對細胞株作用之適當濃度 48
二、 二維差異電泳 (2D-DIGE)分析EEAC對細胞株之蛋白質表現量差異 49
三、 介質輔助雷射脫附游離/飛行時間質譜 (MALDI-TOF-MS)鑑定表現量差異之蛋白質身分 53
四、 差異蛋白質之位置與功能分類 59
1. 位置與功能分類 59
2. 細分功能之蛋白質表現量變化 64
3. 差異蛋白質之關聯性 65
五、 以西方點墨法驗證 (validation)所鑑定之蛋白質 71
六、 以西方點墨法驗證EEAC誘導內質網壓力 81
伍、 討論 83
陸、 結論 88
柒、 參考文獻 89
捌、 附錄 96
附件 一、以胜肽質量指紋分析鑑定Chang Liver與Chang Liver-EEAC之蛋白質表現量差異結果。總共鑑定出82個差異蛋白質。 96
附件 二、以胜肽質量指紋分析鑑定C3A與C3A-EEAC之蛋白質表現量差異結果。總共鑑定出125個差異蛋白質。 108
附件 三、以胜肽質量指紋分析鑑定HepG2與HepG2-EEAC之蛋白質表現量差異結果。總共鑑定出125個差異蛋白質。 125

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