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研究生:黃鈺雯
研究生(外文):Yu-Wen Huang
論文名稱:在神經膠質瘤細胞中抑制Pin1的表現會增加細胞對放射線的敏感性以及降低幹細胞標誌CD133和Sox2的蛋白表現量
論文名稱(外文):Inhibition of Pin1 Enhances Radioresistance and Reduces CD133 and Sox2 Expression in Glioblastoma Cells
指導教授:陳一村
指導教授(外文):I-Tsuen Chen
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:醫學生物技術暨檢驗學系暨研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2010
畢業學年度:98
語文別:英文
論文頁數:65
中文關鍵詞:神經膠質瘤細胞放射線Pin1CD133Sox2
外文關鍵詞:GlioblastomaRadiationPin1CD133Sox2
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Pin1 為 PPIase (peptidyl-prolyl isomerase) 家族的異構酶,可以特異性的辨認某些被磷酸化的蛋白 Ser/Thr-Pro motifs,並且引起此 motif 的構型在 cis 以及 trans 之間的轉換,進而去影響蛋白功能。許多參與細胞週期調控、DNA 損傷反應、轉錄調節和神經生長的蛋白,例如 Cyclin D1, β-catenin, p53 都會被 Pin1 辨認而影響。多形性膠質母細胞瘤 (Glioblastoma multiforme, 簡稱 GBM) 在原發性腦瘤中是最常見且惡性程度最高的一個類型。CD133 被視為癌症幹細胞的重要標誌之一,且表現 CD133 的膠質瘤細胞被認為在腫瘤的復發以及對放射性的抵抗性扮演著重要的角色。所以我們研究 Pin1的表現對於神經膠質瘤細胞對於放線抵抗性以及幹標誌基因 CD133 和 Sox2 蛋白表現的影響。
實驗結果顯示,Pin1 在表現 CD133 的膠質瘤細胞 (S1 和 S1R1) 中表現量較 GBM8401 細胞高。而在 GBM 細胞中 Knockdown Pin1 的表現量會增加細胞對放射線的敏感性,而外加入 Pin1 至 GBM 細胞中則會降低細胞對放射線的敏感性。在表現 CD133 的膠質瘤細胞 (S1 和 S1R1) 中,降低 Pin1 的表現會降低一些幹細胞標誌基因的表現例如 CD133, Sox2 等。而將 Pin1 knockdown 也會降低 β-catenin 的表現,而活化或抑制 β-catenin 會影響 Sox2 的蛋白表現但 Pin1 的蛋白表現則不受到影響。由我們的結果建議,Pin1 可能作用於 β-catenin 的上游進而影響 Sox2 的表現。除此之外,利用免疫共沉澱的方法,我們的結果顯示 Pin1 可能藉由直接與 Sox2 蛋白的互相作用來影響其蛋白穩定度。

Pin1, a peptidyl-prolyl isomerase, specifically recognizes the phosphorylated Ser/Thr-Pro motifs and induces cis/trans isomerization of proline amide bonds contained within the target proteins, such conformational changes have profound effects on the function of Pin1 substrates. Several phosphoproteins involved in cell cycle control, DNA damage responses, transcriptional regulation and neuronal survival including Cyclin D1, β-catenin, p53 are recognized and affected by Pin1. Glioblastoma multiforme (GBM), the most common primary brain tumor, is rapidly fatal. CD133 has been considered as an important marker for cancer stem-like cells, and CD133-expressing glioma cells are known to play a key role in tumor recovery and radioresistance. Here, we investigated the effects of Pin1 expression on radiosensitivity and CD133 and Sox2 expression in Glioblastoma cells.
We showed that enhanced Pin1 expression occurred in CD133-expressing glioblastoma cells (S1 and S1R1) compared to GBM cells. Knockdown of Pin1 in GBM cells increased their sensitivities to radiation, whereas over-expression of Pin1 reduced radiosensitivity. Knockdown of Pin1 decreased several stemness gene expression including CD133, Sox2 etc. Pin1 knockdown also reduced β-catenin expression, where activation or inhibition of β-catenin affected the Sox2 protein expression but not Pin1 expression. This suggests that Pin1 acted at upstream of β-catenin and subsequently affected Sox2 expression. On the other hand, by co-immunoprecipitation assay, we showed that Pin1 might directly interact with Sox2 protein and altered its stability.

Abstract 3
Chinese Abstract 4
Introduction 5
Glioblastoma Multiforme 5
Pin1 6
CD133 7
Sox2 9
Specific Aims 10
Materials and Methods 11
Results 22
Knockdown and over-expression of Pin1 in GBM cells affect their sensitivities to radiation 22
The effects of Pin1 knockdown on growth curve, protein expression and cell cycle distribution in S1 and S1R1 cells 23
The effects of Pin1 knockdown on sphere formation ability in S1、S1R1 cells 23
The effects of Pin1 knockdown on stem cell markers in S1、S1R1 cells 24
The effects of knockdown or over-expression of Sox2 on growth curve and Pin1 protein expression in S1 cells 24
Pin1 affects the level of β-catenin protein expression in S1 cells 25
β-catenin affects the level of Sox2 protein expression in S1 cells 26
The effect of over-expression β-catenin on Sox2 promoter activity 26
Pin1 may directly interact with Sox2 in S1 cells 27
Discussion 28
References 31
Figures 38
Appendix 49

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