根據中華民國101年行政院衛生署十大癌症死因統計，肝癌佔癌症主要死因第二位，更高居全世界排名第四位，所以在臺灣如何維護肝臟健康是值得重視的議題。近年研究發現，臺灣特有之牛樟芝具有護肝、抗發炎、抗B型肝炎病毒、抗癌等生理活性，其主要活性成分為多醣體、苯類、三萜類、固醇類等，又因三萜類通常具有良好的抗癌效果而備受矚目。因此，本研究欲探討由椴木栽培之牛樟芝子實體中純化出含量最多之麥角甾烷型三萜類─antcin K對人類肝癌Hep 3B細胞株之抗癌活性及其分子機制。結果指出，antcin K能有效抑制Hep 3B細胞存活率及促使Hep 3B細胞膜之磷脂醯絲胺酸外翻、染色質濃縮、DNA損傷，但不會明顯地增加細胞中自噬體生成或導致細胞膨脹而破損，故antcin K誘導Hep 3B細胞死亡之主要模式為細胞凋亡，而不是自體吞噬或細胞壞死。深入探討其分子機制後發現，antcin K首先可促進Hep 3B細胞中ROS生成與降低ATP水平而導致內質網壓力產生，內質網壓力伴隨著不完全摺疊反應相關蛋白CHOP表現量上升，進而抑制抗凋亡蛋白Bcl-xL表現量，導致內質網與粒線體膜上之Bax、Bak通道被活化，造成鈣離子由內質網中釋出並部分進入粒線體，最後改變粒線體膜通透性，而釋出促凋亡因子，包括HtrA2/Omi、AIF、Endo-G及cytochrome c，其中cytochrome c進一步活化caspase-9、caspase-3，並切割下游蛋白PARP，最終導致細胞凋亡。綜合以上結果顯示，antcin K可藉由誘導人類肝癌細胞粒腺體及內質網壓力調節之細胞凋亡達到抑癌效果，具有輔助抗癌治療之潛力。

Liver cancer is the second leading cause of cancer deaths in Taiwan as per the 2012 statistics, and ranks the fourth in cancer related mortality in the world. Hence there is a need to focus more on hepato protective foods maintain a healthy liver is a big issue in Taiwan. Recent researches have shown that Antrodia cinnamomea, a Taiwan-specific medicinal mushroom, can manipulate biological activities, include hepatoprotection, anti-inflammation, anti-HBV activity, anticancer activity, etc. The active constituents include polysaccharides, triterpenoids, steroids, etc., and among these, m whose triterpenoids are the most prominent because of their potent anticancer effects. In this study, the anti-liver cancer activity and molecular mechanisms of antcin K, the most abundant ergostsne triterpenoid from the fruiting bodies of basswood cultivated Antrodia cinnamomea was investigated using the human hepatoma Hep 3B cells. The results show that antcin K effectively reduced Hep 3B cell viability within 48 hours. In addition, antcin K induced phosphatidylserine exposure, chromatin condensation, DNA damage, but not significantly increasing autophagosome content or causing cell expansion and cell lysis. So the principal mode of Hep 3B cell death induced by antcin K was apoptosis, rather than autophagy or necrosis. In depth investigation for the molecular mechanisms, revealed that antcin K firstly promoted ROS generation and ATP depletion, lead to ER stress, followed by CHOP expression, down-regulated Bcl-xL and activated Bax/Bak channel to promote intra-cellular calcium ion release from the endoplasmic reticulum then uptake into the mitochondria, resulting in mitochondrial membrane permeability changes. After losing of mitochondrial membrane potential, the apoptosis related factors were released, including HtrA2/Omi, AIF, Endo-G and cytochrome c, the cytochrome c activated the caspase-9, caspase-3, and cut downstream protein PARP, ultimately leading to cell apoptosis. These results suggested that antcin K induced endoplasmic reticulum stress and mitochondria-mediated apoptosis in human hepatoma cells. Coupled with these findings, antcin K has the potential to be complementary agent in liver cancer therapy.

致謝 i
中文摘要 ii
ABSTRACT iii
縮寫對照表 v
圖次 xiii
表次 xvi
第一章 文獻回顧 1
第一節 肝癌 1
一、 肝臟生理功能 1
二、 肝癌流行病學 4
三、 肝癌臨床病理 6
第二節 細胞死亡模式 7
一、 細胞凋亡 8
二、 自體吞噬 18
三、 細胞壞死 20
第三節 內質網鈣離子釋出引發粒線體膜調節之細胞凋亡 21
一、 內質網及粒線體之關聯 21
二、 鈣離子於粒線體之傳送機制 21
三、 內質網壓力連結粒線體調節之細胞凋亡機制 22
第四節 牛樟芝 25
一、 牛樟芝型態與命名 25
二、 牛樟芝人工栽培方法 27
三、 牛樟芝活性成分 28
四、 牛樟芝生理功效 35
第二章 假說與目的 38
第一節 實驗假說 38
第二節 實驗目的 39
第三章 研究架構 40
第四章 實驗材料 42
第一節 藥品與儀器 42
一、 藥品 42
二、 儀器 44
第二節 樣品與細胞株 46
一、 樣品 46
二、 細胞株 46
第五章 方法 47
第一節 樣品製備與分析 47
一、 牛樟芝子實體之乙酸乙酯萃取及管柱層析 47
二、 高效能液相層析分析 47
第二節 抗增殖活性分析 48
一、 細胞之培養與保存 48
二、 細胞存活率分析 49
第三節 細胞死亡模式分析 50
一、 細胞型態觀察 50
二、 細胞大小及顆粒性分析 50
三、 細胞破損程度分析 51
四、 自噬體生成量分析 52
五、 Annexin V/PI分析 53
六、 利用DAPI染色觀察細胞核之型態 54
七、 單細胞膠體電泳法 55
第四節 內質網壓力調節之自體吞噬機制探討 56
一、 活性氧物質生成分析 56
二、 三磷酸腺苷水平分析 57
三、 鈣離子移位分析 58
四、 粒線體鈣離子分布之觀察 59
五、 粒線體膜電位變化之測定 59
六、 蛋白質表現分析 60
第五節 資料統計 63
 

第六章 結果與討論 64
第一節 抗增殖活性評估 64
一、 Antcin K對 Hep 3B細胞存活率之影響 64
二、 本節討論 65
第二節 細胞死亡模式分析 65
一、 Antcin K對Hep 3B細胞形態之影響 65
二、 Antcin K對Hep 3B細胞破損程度之影響 66
三、 Antcin K對Hep 3B細胞自噬體形成之影響 66
四、 Antcin K對Hep 3B細胞膜中Phosphatidylserine（PS）外翻程度之影響 67
五、 Antcin K對Hep 3B細胞中染色質濃縮程度之影響 68
六、 Antcin K對Hep 3B細胞中DNA損傷程度之影響 68
七、 本節討論 69
第三節 、粒腺體及內質網壓力調節之細胞凋亡機制探討 70
一、 Antcin K對Hep 3B細胞活性氧物質生成及三磷酸腺苷水平之影響70
二、 Antcin K對Hep 3B細胞鈣離子訊號之影響 71
三、 Antcin K對Hep 3B粒線體鈣離子分布之影響 71
四、 Antcin K對Hep 3B細胞粒線體膜電位之影響 71
五、 Antcin K對Hep 3B細胞凋亡相關蛋白質表現量之影響 72
六、 本節討論 74
第四節 綜合討論 75
一、 牛樟芝中三萜類純化物抗癌功效與其分子結構之關係 75
二、 牛樟芝中三萜類純化物抗癌機制比較 76
三、 Antcin K與牛樟芝子實體萃取物之抗肝癌機制比較 78
第五節 未來研究 79
一、 Antcin K之後續抗肝癌研究 79
二、 牛樟芝子實體中麥角甾烷型三萜類之後續研究 80
第七章 結論 81
第八章 實驗圖表 83
第九章 參考文獻 101
第十章 附錄 112

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