臺灣博碩士論文加值系統

毒胡蘿蔔素萃取自地中海植物 Thapsia garganica，具有高親脂性的特性而可滲透生物膜。毒胡蘿蔔素透過抑制sarco-內質網鈣離子ATP酶誘發內質網壓力，導致細胞質內鈣離子的增加。已有文獻指出毒胡蘿蔔素會誘導細胞凋亡和細胞自噬。而於我們實驗室發現毒胡蘿蔔素能使A549細胞的hTERT表現減少，進而抑制端粒酶活性。本實驗我們將探討毒胡蘿蔔素的細胞毒性、細胞衰老與表觀遺傳調控hTERT。於本實驗先前研究，松杉靈芝免疫調節蛋白具有抗癌的效果；可於具有野生型上皮生長因子受體之 A549 細胞中，藉由內質網壓力/鈣離子路徑抑制端粒酶活性。因此我們將探討松杉靈芝免疫調節蛋白FIP-gts對於上皮生長因子受體突變肺癌細胞的端粒酶活性與hTERT的影響。在MTT試驗中，毒胡蘿蔔素抑制A549、H1355和H1299的細胞存活率；而FIP-gts可減少A549、H1975 和HCC827的細胞存活率，然而H1650細胞不受抑制。於細胞群落形成實驗，毒胡蘿蔔素抑制A549細胞群落的生成。自噬抑制劑3-MA、Chloroquine和Bafilomycin A1被使用於釐清毒胡蘿蔔素誘導的細胞死亡途徑。然而只有3-MA為自噬起始抑制劑，增加了毒胡蘿蔔素誘導的殺傷作用。利用細胞流式儀分析偵測毒胡蘿蔔素誘導的活性氧與衰老。不同於大部分基因，啟動區高度甲基化啟動hTERT表現。使用染色體端粒酶重覆增幅步驟、反轉錄酶鏈聚合酶連鎖反應與定量聚合酶連鎖反應偵測毒胡蘿蔔素或FIP-gts處理下，肺癌細胞的端粒酶活性和hTERT表現。使用西方點墨法偵測毒胡蘿蔔素或共處理5-Azadc，A549細胞之hTERT、端粒重覆序列结合因子1與2的表現。結果顯示5-Azadc並不會影響毒胡蘿蔔素抑制的端粒酶活性與hTERT表現。DNA甲基轉移酶在甲基化DNA上扮演重要角色。於反轉錄酶鏈聚合酶連鎖反應和西方點墨實驗，毒胡蘿蔔素與5-Azadc 共同處理減少A549細胞中DNMT1和DNMT3B的表現，但不改變DNMT3A。為了詳盡的研究甲基化狀態，利用亞硫酸氫鹽測序分析細胞中毒胡蘿蔔素對hTERT啟動區(-196到+46)甲基化程度影響，發現毒胡蘿蔔素不會誘導hTERT啟動區特定位點CpG甲基化。報導基因分析用於調查轉錄因子於hTERT啟動區活性調控的影響，毒胡蘿蔔素可抑制不同片段(-548、-212、-196與-155) hTERT啟動區活性。我們的研究結果顯示，毒胡蘿蔔素誘導細胞死亡透過抑制hTERT與端粒酶活性。松杉靈芝免疫調節蛋白FIP-gts可抑制細胞的存活與端粒酶活性於上皮生長因子受體突變的肺癌細胞。

Thapsigargin (TG) was isolated from the Mediterranean plant Thapsia garganica. The highly lipophilic characteristic of TG accounts for their excellent penetration of biological membranes. TG can induce ER Stress and increase intracellular calcium through inhibiting sarco-endoplasmic reticulum Ca2+-ATPases. It has been reported that TG induces apoptosis and autophagy. In our previous study, TG inhibits telomerase activity by decreasing hTERT expression in A549 cells. In this study, we investigated the effects of TG on cytotoxicity, cell senescence and epigenetic regulation of hTERT. In our previous studies, fungal immunomodulatory protein Ganoderma tsugae (FIP-gts) has anticancer effects. FIP-gts can inhibit telomerase activity via ER Stress/calcium pahway in wide-type EGFR A549 cells. In this study, we investigated the effects of FIP-gts on telomerase activity and hTERT expression in EGFR mutation lung cancer cells. On MTT assay, the cell viability was reduced by TG in A549, H1355 and H1299 cells and reduced by FIP-gts in A549, H1975 and HCC827 cells. However, FIP-gts did not inhibit cell survival in H1650 cells. On clonogenic assay, TG inhibited A549 cell colony formation. Several autophagy inhibitors, 3-methyladenine (3-MA), chloroquine (CQ), and bafilomycin A1 (BafA1) were used to clarify the role of autophagy in TG-induced cell death. However, only 3-MA, an autophagy initiation inhibitor, enhanced the TG-induced cell-killing effect. The flow cytometry analysis was performed to detect the TG-induced ROS and senescence. Different from most of the genes, promoter hypermethylation turns on the hTERT expression. The TRAP, RT-PCR and Real Time PCR were used to analyze telomerase activity and hTERT expression in lung cancer cells treated with TG or FIP-gts. The western blot assay was performed to detected hTERT, TRF1 and TRF2 expression in A549 cells treated TG with or without 5-Azadc. The results demonstrated that 5-Azadc did not affect the TG-inhibiting telomerase activity and hTERT expression. DNA methyltransferase(DNMTs) enzyme are plays an important role that methylated genomic DNA. On RT-PCR and western blot assay, TG and 5-Azadc co-treatment downregulated the expressions of DNMT1 and DNMT3b, but did not alter the DNMT3a in A549 cells. To study the methylation patterns in more detail, bisulfite sequencing analysis confirm the hTERT promoter region (-196 form +46) in TG-treated cells. TG did not induce the methylation of site-specific CpGs on the hTERT promoter. The reporter assay was used to investigate of effect of transcription factors on hTERT promoter activity regulation. Thapsigargin inhibited the transcriptional activities of hTERT promoter (-548, -212, -196 and -155). Our results suggested that TG induces cell death via inhibited hTERT and telomerase activity. FIP-gts can inhibit cell survival and telomerase activity in EGFR mutation lung cancer cells.

第一章緒論 1
一 肺癌 1
二 內質網壓力 2
三 真菌免疫調節蛋白 (FIP) 4
四 毒胡蘿蔔素(Thapsigargin) 5
五 端粒、端粒酶與腫瘤的關係 6
六 細胞衰老(cellular senescence) 9
七 表觀遺傳修飾機制調控基因表現 10
第二章 縮寫表 (Abbreviation) 12
第三章 研究動機 14
第四章 研究材料與研究方法 15
ㄧ 細胞株 (Cell lines) 15
二 藥品試劑 18
三 細胞存活試驗 20
四 細胞群落生成能力分析(Clonogenic assay) 21
五 染色體端粒酶重覆增幅步驟（Telomeric Repeat Amplification Protocol, TRAP assay） 22
六 衰老相關的β-半乳糖苷酶活性分析 23
七 活性氧物種(ROS)生成之測定 25
八 西方點墨法 26
九 反轉錄酶鏈聚合酶連鎖反應(RT-PCR) 28
十 定量聚合酶連鎖反應(Real-time PCR) 36
十一 報導基因分析 37
第五章 結果 39
ㄧ Thapsigargin對非小細胞肺癌細胞造成細胞毒殺性 39
二 Thapsigargin毒性抑制A549細胞生長 40
三 Thapsigargin抑制非小細胞肺癌細胞的端粒酶活性 40
四 ROS對Thapsigargin於A549癌細胞的細胞毒殺性與端粒酶活性之影響 41
五 化療藥物對Thapsigargin於A549癌細胞的細胞毒殺性之影響 42
六 抑制自噬作用對Thapsigargin於A549癌細胞的細胞毒殺性之影響 42
七 Thapsigargin對A549細胞於細胞自噬的影響 43
八 表觀遺傳修飾抑制劑對Thapsigargin於A549癌細胞的細胞存活率之影響 44
九 5-Azadc抑制劑對A549細胞於細胞型態的影響 44
十 5-Azadc抑制劑對A549細胞於端粒酶活性之影響 45
十一 Thapsigargin對A549細胞衰老之影響 45
十二 Thapsigargin合併5-Azadc抑制劑對A549細胞於hTERT、DNMT1蛋白表現之影響 46
十三 Thapsigargin合併TSA對A549細胞的Acetyl-Histone 3、Acetyl-Histone 4蛋白表現之影響 46
十四 Thapsigargin對A549細胞的TRF1、TRF2、CHOP與γH2AX蛋白表現之影響 47
十五 Thapsigargin合併5-Azadc抑制劑對A549細胞於DNMT與hTERT mRNA表現之影響 48
十六 Thapsigargin對肺癌細胞hTERT promoter甲基化之影響 48
十七Thapsigargin調控hTERTP promoter 轉錄活性 49
十八Thapsigargin抑制hTERT　promoter的轉錄因子 50
十九Thapsigargin合併BAPTA-AM對A549細胞端粒酶活性與hTERT mRNA表現的影響 50
二十FIP-gts抑制端粒酶活性 51
二一FIP-gts對具有EGFR 突變的非小細胞肺癌之細胞毒殺性的影響 52
二十二FIP-gts對具有EGFR 突變的非小細胞肺癌之端類酶活性的影響 52
二十三FIP-gts對具有EGFR 突變的非小細胞肺癌之hTERT mRNA 的影響 53
第六章 討論 54
第七章 圖表 64
第八章 附表 101
第十一章 參考文獻 103

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