臺灣博碩士論文加值系統

肝癌 (Hepatocellular carcinoma)在造成國人癌症相關死亡數量排名第二的癌症。目前晚期肝癌的治療藥物效果欠佳且具有強烈的副作用，因此目前對於改善肝癌治療效果的需求十分迫切。紫檀芪 (pterostilbne)除了具有降血糖、降血壓以及抗發炎能力之外，也被發現具有抗腫瘤轉移以及增生的能力。然而，紫檀芪對於肝癌細胞增生能力的抑制效果和詳細機轉還尚待釐清。我們發現紫檀芪可以抑制肝癌細胞的增生。但卻不會起肝癌細胞的細胞凋亡 (apoptosis)以及壞死性凋亡 (necroptosis)反應，而是活化肝癌細胞的自噬 (autophagy)反應。同時，紫檀芪會造成肝癌細胞內質網壓力 (endoplasmic reticulum-stress)上升，進而促進ATF4結合到LC3啟動子上的遠端結合位進而增加LC3之表現。而透過siRNA抑制ATF4和eIF2α之表現後，可抑制紫檀芪所誘導的自噬性死亡。以Salubrinal抑制eIF2α之去磷酸化後，則是會促進紫檀芪自噬性細胞死亡。顯示出p-eIF2α/ATF4/LC3路徑是紫檀芪誘導肝癌細胞自噬性死亡的主要機制。同時SK-Hep-1的裸鼠異種移植以及小鼠的毒性實驗則是證實了紫檀芪在體內實驗模式中同樣具有抑制肝癌細胞增生的能力，並且不會對宿主造成毒害。為紫檀芪作為肝癌治療藥物的潛力提供有利的證據。

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Due to a lack of early diagnosis tools and the poor effect alongside with server adverse effects of current treatment, improvement of current HCC treatment strategy is urgently needed. Pterostilbene (PT) have been found to possess anti-glycemic, anti-inflammation activities, many studies have also shown that PT possess anti-metastatic and anti-proliferation abilities. However, the effect of PT on the proliferation of HCC remains unclear. In our research, PT is shown to inhibit the proliferation without inducing apoptosis or necroptosis, but induced autophagy of HCC cell lines. Pharmacological inhibition of autophagy hindered the PT induced autophagic-cell death. In the meantime, we found out that PT also induces endoplasmic reticulum-stress (ER-stress), and increases the binding of ATF4 on the distal binding site on the LC3 promoter. Furthermore, downregulation of ATF4 and eIF2α through siRNA suppressed the PT induced autophagic-cell death. Phosphorylation eIF2α is vital to the correct expression of ATF4. Enhanced phosphorylation of eIF2α by Salubrinal (Sal) can further increase PT-induced autophagic-cell death. Taken together, our data indicated PT induced autophagic-cell cell death through the regulation of p-eIF2α/ATF4/LC3 pathway. Xenograft experiment of SK-Hep-1 and the toxicity evaluation further confirmed the anti-tumor proliferation activity and the safeness of PT in vivo. In conclusion, our study provides solid evidence for the potential of PT as a novel HCC treatment.

謝誌 i
中文摘要 ii
Abstract iii
縮寫表 iv
壹、緒論 1
一、肝癌 (Liver Cancer) 1
1. 肝癌的流行病學及簡介 1
2. 肝癌的風險因子 3
3. 肝癌的診斷和預防 4
4. 肝癌的分期與治療 5
二、紫檀芪 (pterostilbene) 9
1. 生物可利用性 (bioavailability)與毒性 9
2. 降血糖能力 10
3. 抗氧化能力和抗發炎能力 10
4. 抗腫瘤能力 11
三、計畫性細胞死亡 (Programmed cell death) 15
1. 細胞凋亡 (Apoptosis) 15
2. 細胞自噬 (Autophay) 19
四、內質網壓力 (endoplasmic reticulum-stress, ER-Stress) 25
1. 內質網壓力來源 25
2. 未折疊蛋白反應 (unfolded protein response, UPR) 26
3. UPR誘導之計畫性細胞死亡 29
貳、研究動機 31
參、實驗材料與方法 32
一、實驗材料 32
二、實驗儀器 36
三、實驗方法 38
1. 細胞培養 38
2. siRNA轉染 (siRNA transfection) 40
3. 細胞毒性分析 (Cytoioxicity analysis) 40
4. 細胞群落形成能力分析 (Colony formation assay) 41
5. 細胞凋亡分析 (Apoptosis analysis) 41
6. 細胞週期分析 (Cell cycle analysis) 42
7. 酸性胞器 (acidic vesicular organells, AVO)生成分析 42
8. 細胞超微結構分析 (Cellular ultrastructure analysis) 43
9. 西方墨點法 (Western blot analysis) 43
10. 內質網擴張定量分析 (ER-expansion analysis) 46
11. 氧化壓力定量分析 47
12. 免疫螢光染色 (Immunofluorescence staining) 48
13. 染色體免疫沉澱分析 (Chromatin immunoprecipitation, ChIP) 48
14. 細胞核細胞質蛋白質分離 (Nuclear protein isolation) 51
15. 癌細胞異種移植體內生長實驗 52
16. 體內安全性分析 (in vivo safety analysis) 52
17. 免疫組織染色 (Immunohistochemistry staining) 53
18. 統計分析 (Statistical analysis) 54
肆、實驗結果 55
一、分析紫檀芪對肝癌細胞株細胞毒性 55
二、探討紫檀芪抑制肝癌細胞增生之機制 55
三、探討紫檀芪是否誘導肝癌細胞產生自噬反應 56
四、探討紫檀芪是否透過細胞自噬造成肝癌細胞死亡 57
五、探討晚期細胞自噬與紫檀芪誘導之胞自噬性死亡之間的關聯 58
六、分析紫檀芪對內質網大小之影響。 59
七、探討氧化壓力上升是否與紫檀芪造成之細胞死亡有關 59
八、分析紫檀芪對肝癌細胞內質網壓力相關蛋白表現的影響 60
九、探討紫檀芪是否透過活化內質網壓力誘導細胞自噬 60
十、分析紫檀芪對於ATF4以及LC3細胞內分佈的影響 61
十一、分析紫檀芪對於ATF4結合LC3啟動子的影響 61
十二、探討紫檀芪是否透過ATF4造成肝癌細胞自噬性死亡 62
十三、探討紫檀芪是否透過eIF2α造成肝癌細胞自噬性死亡 62
十四、探討eIF2α磷酸化對紫檀芪造成之肝癌細胞自噬的影響 63
十五、探討eIF2α磷酸化對紫檀芪造成之肝癌細胞自噬性死亡的影響 64
十六、探討增加eIF2α磷酸化增加紫檀芪造成的肝癌自噬性細胞死亡之機制 65
十七、以小鼠動物實驗模式檢測紫檀芪的毒性 65
十八、以小鼠動物實驗模式驗證紫檀芪抑制肝癌細胞增生的能力 66
伍、討論 67
陸、圖表說明 75
柒、參考文獻 112

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