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研究生:黃冠杰
研究生(外文):Kuan-Chieh Huang
論文名稱:下調雙調蛋白促進阿黴素在膠質瘤細胞中透過調節內質網壓力誘導細胞凋亡及自噬死亡
論文名稱(外文):Knockdown of amphiregulin promotes doxorubicin-induced apoptotic and autophagic death via modulation of endoplasmic reticulum stress in glioma cells
指導教授:陳瑞傑林芸薇
指導教授(外文):Jui-Chieh ChenYun-Wei Lin
學位類別:碩士
校院名稱:國立嘉義大學
系所名稱:生化科技學系研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
畢業學年度:104
語文別:中文
中文關鍵詞:雙調蛋白膠質瘤細胞細胞凋亡細胞自噬
外文關鍵詞:Glioblastoma multiformeDoxorubicinAmphiregulinapoptosis
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膠質母細胞瘤(Glioblastoma multiforme,GBM)是一種常見的惡性腦瘤,其存活率非常低,主要是因為GBM對於目前的治療具有極高的抗藥性且容易再度復發。阿黴素(Doxorubicin,DOX)在過去的十年間用於治療各種癌症,例如:骨癌、膀胱癌、乳癌…等。雙調蛋白(Amphiregulin,AR)是表皮生長因子受體(Epidermal groth factor receptor,EGFR)的配體(Ligand),AR牽涉到許多細胞的過程,例如:抗藥性、轉移能力、細胞分化…等。內質網(Endoplasmic reticulum)是一個動態且複雜的胞器,內質網的功能包括:蛋白質的摺疊、鈣離子的儲存、脂肪及碳水化合物的代謝。不同的細胞壓力像是細胞內鈣離子的擾動、氧化還原反應失衡,都會造成蛋白質糖化或蛋白質摺疊的缺陷,造成未折疊或折疊錯誤的蛋白質累積在內質網腔室中,這種反應稱之為內質網壓力(ER stress)。
因此本研究第一次描述AR對於GBM受到DOX攻擊時所誘發的細胞凋亡及自噬死亡是透過內質網壓力。Knockdown AR導致GBM對於DOX更加敏感,此外在Knockdown AR的GBM中可以觀察到處理DOX會增加自噬作用相關蛋白LC3-II及凋亡蛋白Caspase-3活化,其相對量都比野生型的GBM還要來的多。
這些研究表明AR會去調節內質網壓力,影響細胞凋亡及自噬,這在未來可以作為一個藥物標靶的目標。
第一章 緒論(Introduction) 1
1.腦瘤 1
2.腦瘤分類(Classification of brain tumor) 2
3.多形性膠質母細胞瘤(Glioblastoma multiforme,GBM) 3
4.阿黴素(Doxorubicin,Dox) 4
5.雙調蛋白(Amphiregulin,AR) 5
6.內質網壓力(Endoplasmic reticulum stress,ER-stress) 6
7.細胞凋亡(Apoptosis) 8
8.細胞自噬(Autophagy) 9
第二章 材料與方法(Materials and Methods) 11
2-1實驗材料與試劑 11
2-1-1 藥品 11
2-1-2 實驗材料配方 12
2-1-3 抗體 18
2-1-4 實驗儀器 18
2-2 實驗方法 19
2-2-1 細胞培養(Cell culture) 19
2-2-2 細胞計數 20
2-2-3.質體transformation 20
2-2-4.質體抽取 21
2-2-5. 細胞轉染及製作Lentivirus 22
2-2-6. Gene Knockdown 22
2-2-7.細胞存活率分析MTT 23
2-2-8.細胞群落形成分析法(colony forming assay) 23
2-2-9.西方墨點法(Western blot analysis) 24
第三章 結果(Result) 26
3-1 癌細胞的阿黴素抗藥性可能與雙調蛋白相關。 26
3-2 利用帶有shRNA的慢病毒Knock-downU87細胞中AR的表現量,並增加U87細胞對於阿黴素的敏感性 。 26
3-3. 細胞群落分析。 27
3-4. 阿黴素誘導U87細胞表現內質網壓力相關蛋白。 27
3-5阿黴素誘導U87細胞進行自噬作用 29
3-6阿黴素藉由ER stress誘導U87細胞凋亡 29
第四章 討論(Discussion) 30
參考文獻(References) 35
附錄(Appendix) 43
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18. Hobor S, V.E.B., Crowley E, Misale S, Di Nicolantonio F, Bardelli A., TGFα and amphiregulin paracrine network promotes resistance to EGFR blockade in colorectal cancer cells. Clinical cancer research : an official journal of the American Association for Cancer Research, 2014 Dec 15.
19. Hetz, C., The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol, 2012. 13(2): p. 89-102.
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