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研究生:藍倢妤
研究生(外文):Chieh-Yu Lan
論文名稱:槲皮素調控高度醣化終產物受器表現對人類胰臟癌細胞抗藥性及細胞死亡之研究
論文名稱(外文):Regulatory effect of quercetin on receptor for advanced glycation end products expression for drug resistance and cell death in human pancreatic cancer cells
指導教授:顏國欽顏國欽引用關係
口試委員:潘敏雄翁家瑞吳啟豪
口試日期:2015-07-20
學位類別:碩士
校院名稱:國立中興大學
系所名稱:食品暨應用生物科技學系所
學門:農業科學學門
學類:食品科學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:中文
論文頁數:122
中文關鍵詞:高度醣化終產物受器槲皮素胰臟癌抗藥性細胞凋亡自噬
外文關鍵詞:RAGEquercetinpancreatic cancerdrug resistanceapoptosisautophagy
相關次數:
  • 被引用被引用:4
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  • 下載下載:33
  • 收藏至我的研究室書目清單書目收藏:0
由於胰臟癌發生初期,病灶難以發現,為常見腫瘤中惡性程度最
高,而其高度抗藥性表現導致其治癒率低且存在高死亡率,故有效對
抗胰臟癌是值得被探討的議題之一。研究指出高度醣化終產物受器
(Receptor for advanced glycation endproducts, RAGE) 之活化會誘發氧化壓力、體內慢性發炎反應及癌症等的發展過程有關聯性。高度表現RAGE 會增強腫瘤形成時之發炎致癌因子,達到促癌化過程與增加癌症治療之抗藥性產生。因此,RAGE 可作為癌症治療之潛力標靶蛋
白,透過抑制RAGE 活化而降低癌細胞對藥物之抗藥性的可能性。
槲皮素 (quercetin) 為黃酮類化合物之重要植化素,具有抗氧化、抗
發炎、抑制腫瘤細胞侵入轉移以及誘導癌細胞凋亡之功效。本研究目
的乃探討 RAGE 於人類胰臟癌細胞 MIA Paca-2 中的表現量,對存
活率及死亡路徑調控之影響,並透過建立抗藥性細胞株,驗證 RAGE
過量表現造成抗藥性之確實性。更進一步分析槲皮素是否透過影響
RAGE 表現量而達到抗胰臟癌之效果。
實驗結果指出利用基因弱化 (gene knockdown) 方式降低胰臟癌
細胞中RAGE 表現量,其可增加化療藥物 Gemcitabine (GEM) 對癌
細胞的死亡率,以提高對 GEM 之敏感性。RAGE 表現量多寡會影
響 GEM 所造成的細胞死亡模式,研究發現RAGE 基因弱化會促進
自噬作用產生,以及使細胞走向凋亡路徑。另外,可透過影響轉錄因
子 Nuclear factor-kappaB (NF-κB) 之轉位,減少 NF-κB 進入核內,
達到降低轉錄作用而調控下游分子與凋亡、自噬相關之基因表現。此
外,RAGE 基因弱化會增加鈣黃綠素 (calcein) 螢光表現量,此結果
表示會減少抗藥性蛋白 MDR1 (P-glycoprotein) 產生;並且增加藥物
通道蛋白 Human concentrative nucleoside transporter family 3 (hCNT3)之基因表現,使藥物進入得多,以達到毒殺胰臟癌細胞之效果。再者,槲皮素其能有效降低胰臟癌細胞內 RAGE 基因與蛋白之生成量,且能透過抑制 RAGE 基因表現,提升細胞凋亡與自噬作用,減少NF-κB 轉位能力,增加胰臟癌細胞之死亡率達到抗癌的功效。本研究亦建立具 GEM 抗藥性之人類胰臟癌細胞株 MIA Paca-2 GEMR,並
發現 MIA Paca-2 GEMR 細胞確實具較高之 RAGE 與 MDR1 表現
量,並透過RAGE 基因弱化方式反向驗證,經結果證實 RAGE 高量
表現的確會增加胰臟癌細胞對 GEM 之抗藥性。
綜合上述結果,RAGE 確實可作為癌症治療之指標,透過抑制RAGE 表現,可以增加細胞凋亡以及自噬作用,提升胰臟癌細胞之死亡,減少其所產生之抗藥性表現。介入槲皮素達成抑制RAGE 表現效果,進而提高抗胰臟癌作用,同時賦予槲皮素新的輔助抗癌潛力。

Pancreatic cancer (PC) is one of the most aggressive types of cancer but its poor prognosis is due to the lack of disease-specific signs and symptoms to avoid early diagnosis and curative treatment. The survival rate of the patient with PC is much lower because of the almost complete chemoresistance. The anti-pancreatic cancer effect is indeed needed to further investigate. Receptor for advanced glycation end products (RAGE) activation has been shown to be induced by oxidative stress, inflammatory diseases and linked to the development and progression of cancers. RAGE is considered to enhance tumor formation in an inflammatory carcinogen model and has been demonstrated to be associated with increased resistance to chemotherapy. Therefore, the regulation of RAGE expression is a potential target of cancer therapy, and suppression of RAGE activation might be a strategy to reduce chemoresistance. Quercetin is found to possess antioxidant and anti-inflammatory effect, anti-tumor invasion and induction of cell apoptosis. Therefore, the aim of this study was to verify the regulatory effect of RAGE expression on cell survival and regulation of cell death signaling in human pancreatic carcinoma MIA Paca-2 cells. Moreover, gemcitabine (GEM)-resistant cells were also established by subculturing through incrementally increasing GEM concentrations. The inhibitory effect and underlying mechanism of RAGE on anti-pancreatic cancer effect was also explored.
The results showed that effect of RAGE knockdown on Mia PaCa-2 cells increased the GEM sensitivity and promoted cell death. RAGE expression contributed to the modes of cell death and their associated pathway. It is reported that effect of RAGE knockdown promoted autophagy and induced cell apoptosis. Thus, decreasing the level of RAGE expression reduced NF-κB translocation to regulate gene transcription of the downstream molecules related with apoptosis and autophagy. In addition, RAGE knockdown decreased MDR1 expression which was analyzed by calcein fluorescence and increased hCNT3 expression to improve efficacy of drugs. To further investigate GEM resistance of PC, GEM-resistant cells was established to confirm its relevance. The results showed that GEM-resistant MIA Paca-2 cells (MIA Paca-2 GEMR) exhibited high expression of RAGE and MDR1. Based on the findings, RAGE expression is involved in chemoresistance of GEM.
In conclusion, RAGE could be a target to PC treatment. Suppression of RAGE expression reduced PC drug resistance. Quercetin is a phytochemical and its capability inhibits RAGE expression to enhance anti-pancreatic cancer effect. Therefore, it is suggested that quercetin potentially offer against PC therapy through modulating RAGE level.

全文摘要 i
目次 v
圖次 viii
縮寫表 xi
前言 1
第一章 文獻整理 2
壹、胰臟癌 3
貳、細胞之生長與死亡 4
一、 細胞週期之調控 ……………………………………………4
二、 細胞凋亡之調控 ……………………………………………5
三、 細胞自噬之程序 ……………………………………………6
四、 細胞凋亡與癌症治療 ……………………………………….7
參、RAGE (Receptor for advanced glycation endproducts) ……...10
一、結構與活化機制 ………………………………………………10
二、RAGE與癌症相關研究 ……………………………………...11
肆、癌症與抗藥性 14
伍、胰臟癌之抗藥性機轉 16
一、 異常基因表現 ………………………………………………16
二、 相關路徑之調控 ………………………………………….17
三、 基因突變 (Genetic mutations) …………………………….17
四、 腫瘤微環境 …………………………………………………...18
陸、轉錄因子NF-ΚB 21
柒、槲皮素 (quercetin) …………………………………………..23
一、 多酚類化合物抗腫瘤之生理活性 ………………………..23
二、 槲皮素 ………………………………………………………..23
捌、研究目的 25
玖、研究架構 26
高度醣化終產物受器表現之調控對人類胰臟癌細胞死亡及抗藥性之研究 27
摘要 28
Abstract ………………………………………………………….…..29
前言 30
材料與方法 31
結果 41
一、 不同分化程度之胰臟癌細胞 RAGE 表現量 41
二、 MIA Paca-2、BxPC-3 胰臟癌細胞株之 RAGE 基因弱化結果 ……………………………………………………………………...41
三、 RAGE 對人類胰臟癌細胞藥物敏感性之影響 41
四、 胰臟癌細胞 MIA Paca-2 與 BxPC-3 細胞經 RAGE 基因弱化後對細胞死亡之影響 …………………………………………..42
五、 siRAGE 對 MIA Paca-2 細胞 RAGE 蛋白表現量之影響..43
六、 RAGE 基因弱化對細胞自噬之影響 43
七、 RAGE 基因弱化對於調控細胞自噬蛋白表現之影響 44
八、 RAGE 基因弱化對細胞凋亡之影響 44
九、 RAGE 基因弱化對轉錄因子 NF-ΚB 表現之影響 44
十、 siRAGE對鈣黃綠素螢光表現量之影響 ……………………45
十一、siRAGE 對 MIA Paca-2 細胞通道蛋白基因表現之影響….45
十二、siRAGE 對 MIA Paca-2 細胞多重抗藥性蛋白基因表現量之影響 …………………………………………………………………46
一、抗藥性人類胰臟癌細胞株 MIA Paca-2 GEMR 之建立 ……...46
二、MIA Paca-2 GEMR 細胞之鈣黃綠素螢光表現量分析 ……...46
三、胰臟癌 MIA Paca-2 GEMR 細胞株 RAGE 之蛋白表現量 …47
四、siRAGE 對 MIA Paca-2 GEMR 細胞藥物敏感性之影響 ……...47
討論 48
槲皮素調控高度醣化終產物受器表現對人類胰臟癌細胞抗藥性及細胞死亡之研究 76
摘要 77
Abstract………………………………………………………………78
前言 79
材料與方法 80
結果 83
一、 槲皮素對胰臟癌細胞中 RAGE 基因及蛋白表現量之影響 83
二、 槲皮素於胰臟癌細胞中對藥物敏感性之影響 83
三、 槲皮素對 MIA Paca-2 細胞死亡之影響……………………84
四、 槲皮素對 MIA Paca-2 細胞自噬小體之影響 …………..84
五、 槲皮素對 MIA Paca-2 細胞自噬之影響……………………84
六、 槲皮素對 MIA Paca-2 細胞凋亡之影響……………………85
七、 槲皮素對 MIA Paca-2 細胞抗藥性之影響 …………….….85
八、 槲皮素對 MIA Paca-2 細胞轉錄因子 NF-κB 表現之影響86
九、 槲皮素對 MIA Paca-2 細胞通道蛋白基因表現之影響……86
十、 槲皮素對 MIA Paca-2 細胞 Multidrug resistance associated proteins (MRPs) 基因表現之影響 …………………………………86
討論 88
總結論 103
參考文獻 104


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