根據過去文獻報導，葉酸缺乏會導致同半胱胺酸引起之氧化壓力堆積，誘使胞內及粒腺體鈣離子失衡，啟動內質網壓力及錯誤摺疊蛋白反應途徑，進而產生癌細胞的程式凋亡。過去我們實驗室發現分化較差的肝癌細胞株 SK-Hep-1 在葉酸缺乏的情況下，不會誘發程式凋亡，可見該細胞株可能在葉酸缺乏情況下，啟動生存機制來幫助其抵抗外來壓力，使其在極惡劣的環境下得以存活。由於SK-Hep-1在葉酸缺乏的情況下啟動了何種存活機制，迄今為止，鮮少報告。近年來報導指出，錯誤摺疊蛋白反應途徑能誘發內質網護送蛋白 GRP-78 的增加，而活化細胞存活的路徑。在本研究中證實，SK-Hep-1在葉酸缺乏下對 cisplatin、taxol、doxorubicin 及 curcumin 等抗癌藥物，有藥物耐受性的情形；以及在累積劑量21 Gy 的放射療程下，具有放射抵抗性。這現象指出，葉酸缺乏誘發之存活機轉提供細胞對抗這些藥物及放射療法的能力。我們使用西方點墨法證實，持續低量同半胱胺酸誘發之活性氧的堆積能導致大量的GRP-78 表現及 AKT 磷酸化的增加，而可能導致此細胞具有抗藥及抗放射療法的能力。本研究第一個提供證據顯示，葉酸缺乏誘導抗藥性及抗放射療法的情況，並誘導同半胱胺酸調節GRP-78 的表現，可能是適應葉酸缺乏的保護機制。

Our group recently found that a poorly-differentiated HCC, SK-Hep-1, could evade folate deficiency-induced apoptosis. However, the underlying mechanism associated with this hitherto unreported phenomenon is thus far elusive. Since we noted that Hep-G2 cells grown under folate deficient condition could elicit an accumulation of cytosolic and mitochondrial calcium (Ca2+) levels. This implied that homocysteine (Hcy)-induced ROS production could serve as a signal to modulate ER Ca2+ homeostasis leading ER stress and unfolded protein response (UPR). The activation of the UPR may lead to cell survival pathway by triggering the synthesis of ER chaperon proteins such as GRP-78 (also referred to as Bip). In this study, we present evidence to substantiate that SK-Hep-1 cultivated under folate deficient condition can engender drug resistance acquisition to anti-cancer drugs including cisplatin, taxol, doxorubicin and curcumin and radio-resistance acquisition (a fractionation dose of 3 × 7Gy). This phenomenon implied that folate deficient condition may be able to activate a survival pathway rendering cells resistant to these drugs and radiotherapy. Using western blotting technique, we demonstrated that sustained low levels of Hcy-induced ROS accumulation could result in a drastic increment of ER chaperon GRP-78 and phosphate-AKT expression which correlate in parallel with the induction of the drug resistance and radio-resistance acquisition. Taken together, this study provides the first evidence that folate deficiency can induce drug resistance and radio-resistance acquisition and Hcy-mediated expression of GRP-78 which may confer a protective pathway underlied this phenomenon.

指導教授推薦書……………………………...…………………………
口試委員審定書…………………...……………………………………
授權書………………………………...…………………………………iii
誌謝…………………………………...……………………………….iv
中英對照表……………………………...…..………………………….vii
縮寫表…………………………………...…..………………………. ix
中文摘要…………………………………...…………………………..xi
英文摘要……………………………………………………………......xii
目錄………………..…………………………………………………xiii
第一章 簡介………………………………………………………. 1
1.1 葉酸 ( Folic acid, Folate, Folacin, Vitamin B9) ………...... 2
1.1.1葉酸缺乏及氧化-硝化壓力 ( folate deficiency and oxidative-nitrosative stress ) ..…………………........ 3
1.2 內質網壓力 (endoplasmic reticulum stress, ER stress) 及錯誤折疊蛋白反應途徑 (unfolding protein response, UPR).... 5
1.2.1錯誤折疊蛋白反應途徑 (unfolding protein response, UPR) …….…………………………………………… 6
1.2.2葡萄糖調控蛋白78 (glucose-regulated proteins 78, GRP 78；ER chaperone immunoglobin-binging protein, Bip)…8
1.3 -catenin 訊息傳遞路徑 (-catenin signaling cascade) .… 10
1.3.1環氧化酶 (cyclooxygenase-2, COX-2) ………........... 11
1.3.2 Vmentin …………………...…………..……………… 12
1.4 缺氧（hypoxia）及缺氧誘導因子（hypoxia inducible factor-1, HIF-1）……………………………………..………………. 13
1.4.1 缺氧誘導因子 （hypoxia inducible factor, HIF）…… 14
1.5 血管新生因子(angiogensis factors)……………….. 15
1.6 所使用藥物之簡介....................................................... 16
1.6.1 順鉑 (cisplatin)............................................. 16
1.6.2 阿黴素 (doxorubicin).................................. 16
1.6.3 太平洋紫衫醇 (Paclitaxel, Taxol)................. 17
1.6.4 薑黃素 (Curcumin) .................................... 17
1.7 研究目的 (specific aims) ………………………..……..… 20
第二章 材料與方法……………….....……………………………. 22
2.1 實驗材料……………………………………………...…… 22
2.1.1 細胞株與細胞培養基……………………...…..…… 23
2.1.2 西方墨點法所使用之抗體……………….……...…. 23
2.1.3 所使用之藥物……………….……...………………. 23
2.2 實驗方法……………………………………………...…… 24
2.2.1 細胞培養 (Cell culture)…………..….…..........…… 24
2.2.2低氧處理 (Hypoxia)…………..………….…...….… 24
2.2.3 總蛋白萃取 (Total Protein Extraction)..…….…….. 25
2.2.4 核蛋白萃取 (Nuclear Protein Extraction)...……….. 25
2.2.5 蛋白定量 (Quantitative of protein concentration)… 26
2.2.6 西方點墨法 (Western blot)……..……...........…….. 26
2.2.7 EMSA (Electrophorisis Mobility Shift Assay)..…...….….. 27
2.2.8 細胞週期的偵測………………..……...….....…….. 28
2.2.9 細胞內ROS的偵測……………..…....….....…….. 29
2.2.10免疫螢光染色…………………..…....….....…….. 29
2.2.11 ELISA (Interleukin 8 (IL-8) 測定)……........…….. 30
2.2.11 錐藍排除法 (Trypan blue exclusion assay)….….. 30
2.2.12 MTT Assay…………………………………….….. 31
2.2.13統計分析…………………………………….….. 31
第三章 結果………...……………………..………………………. 32
3.1葉酸缺乏影響人類肝癌細胞對各類藥物的敏感性……… 32
3.2 葉酸缺乏影響人類肝癌細胞株對放射線治療的敏感性... 33
3.3 葉酸缺乏導致之惡性化轉移及抗藥性的機制探討.... 33
3.3.1 葉酸缺乏對人類肝癌細胞株的細胞週期及胞內ROS產生之影響………………...…………………...………… 34
3.3.2 在葉酸缺乏下，NFB 及 -catenin 對 SK-Hep-1 的影響………………….……..…………………...………… 35
3.3.3 SK-Hep-1 在葉酸缺乏下，ER stress 相關蛋白的表現情況………………….……..…………………...………… 36
3.3.4 SK-Hep-1 在葉酸缺乏下，磷酸化 AKT 及磷酸化 ERK 的表現情況……..………...……………………………. 36

3.3.5 在葉酸缺乏下，抗細胞凋亡因子 (Bcl-2, survivin) 及 pro-caspase 3 的表現情況……..………...………… 37
3.3.6 在葉酸缺乏下，血管新生因子 (VEGF, IL-8) 的表現情況……..………......................................………… 37
3.3.7 葉酸缺乏細胞在缺氧 (hypoxia) 下誘發 HIF-1 的狀況………………………………………………...…… 38
第四章 討論………...……………………..………………………. 39
4.1 葉酸缺乏增強 SK-Hep-1 惡性化轉移的特性…….…. 39
4.1.1 葉酸缺乏造成的 Oxidative stress 及 ER stress 啟動細胞的生存途徑 (survival pathway)…...……......…... 39
4.1.2 葉酸缺乏增強缺氧下 HIF-1的上升…………… 41
4.2 葉酸缺乏影響人類肝癌細胞 SK-Hep-1 對各類藥物的敏感性……………………………………...................... 41
4.2.1 葉酸缺乏增強 SK-Hep-1 對 cisplatin 的抵抗性... 41
4.2.2 葉酸缺乏增強 SK-Hep-1 對 doxorubicin 的抵抗性...42
4.2.3 葉酸缺乏增強 SK-Hep-1 對 taxol 的抵抗性... 43
4.2.4 葉酸缺乏增強 SK-Hep-1 對 curcumin 的抵抗性….. 44
4.2.5 抗葉酸藥物及茶多酚 (EGCG)……………………….. 45
4.3 葉酸缺乏影響人類肝癌細胞 SK-Hep-1 對放射療法的敏感性……………………………………...................... 45
第五章 結論………...……………………..………………………. 47
第六章 參考文獻….……………………..………………………. 48
第七章 圖表….……………………..……………………...…….... 64
7.1 Figure 1~14………………………………………...............64
7.2 Appendix 1~7……………………………………………..78

胡涵淑，〈p53野生型HepG2經由造血素調控Wnt訊息傳遞影響mdr-1基因表現之機制探討〉長庚大學，碩士論文，民國 94年
王維直，〈探討葉酸缺乏對人類肝癌細胞株Hep G2細胞所引起的同胱胺酸誘導之氧化和硝化壓力以及氧化修飾性蛋白所參與之細 胞凋機制〉長庚大學，碩士論文，民國96年
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