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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 廖憶純(Yi-Chun Liao) | |
dc.contributor.author | Po-Han HUANG | en |
dc.contributor.author | 黃柏翰 | zh_TW |
dc.date.accessioned | 2021-06-17T08:21:45Z | - |
dc.date.available | 2019-08-20 | |
dc.date.copyright | 2019-08-20 | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019-08-13 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/74145 | - |
dc.description.abstract | Cisplatin 是廣泛使用的抗癌藥物,但病患往往會發展出對該藥物的抗性而造成治療失敗,研究發現有許多蛋白質在對 cisplatin 敏感及具抗性的癌症細胞有差異性的表現,這些蛋白質可用來評估 cisplatin 的治療效果或作為治療的標靶。C-terminal tensin like (CTEN) 為tensin家族中的一員,位於集中附著點 (Focal adhesion) 連結胞外基質與細胞骨架,研究顯示它在細胞遷移、增生、附著與癌症發生過程中均扮演重要角色。本實驗室前人的研究發現,CTEN蛋白質會受到DNA damage cascade重要調節因子p53的調控,以cisplatin處理人類正常前列腺細胞RWPE-1,也發現CTEN蛋白質表現量有下降的情形,本研究假設CTEN會參與在p53調控cisplatin誘發的DNA damage下游反應中;然而,本研究發現在人類正常前列腺上皮細胞RWPE-1中,CTEN蛋白質表現量下調可能並不是cisplatin抑制細胞增生與引起細胞凋亡的主要原因。與正常細胞不同的是,以cisplatin處理人類大腸癌細胞HCT116與肺癌細胞A549後,均發現CTEN蛋白質表現量有上升的情形;進一步透過線上資料庫分析發現,CTEN在具有cisplatin抗性細胞株中的表現量會高於其親代細胞;除此之外,我們也發現CTEN在具有cisplatin抗性的癌細胞種類中,其表現量會高於較敏感的其他種類。因此,我們假設CTEN表現量上調與癌細胞的cisplatin抗性有關;然而在實驗方面,透過siRNA干擾技術降低A549中的CTEN表現量後,卻發現細胞對cisplatin的抗性增加,與我們原先預期的結果相反;值得一提的是,cyclin dependent kinase inhibitor p21在knockdown CTEN的組別中表現量也有下降的情形,推測這可能是在knockdown CTEN後造成細胞存活率上升的原因。另一方面,本實驗室前人研究證實CTEN在人類大腸癌細胞HT29細胞核中具有結合DNA的功能,也透過ChIP-NGS技術找出CTEN的結合序列,本研究進一步分析NGS的資料,也發現到其中有一些CTEN的目標調控基因可能參與在與調控cisplatin的抗性有關的DNA修復、細胞增生、細胞週期與細胞凋亡的路徑當中。 | zh_TW |
dc.description.abstract | Cisplatin is one of the most effective broad-spectrum anticancer drugs. However, resistance to cisplatin is observed commonly and is the major cause of treatment failure. Proteins that are differentially expressed in cisplatin-resistant and -sensitive cancer cells are likely to be involved in pathways that modulate cisplatin sensitivity. These proteins are logical candidates for treatment response biomarkers and therapeutic targets. C-terminal tensin like (CTEN) is a member of tensin family that localize to focal adhesion and connect extracellular matrix and intracellular cytoskeleton. CTEN is involved in many cellular processes including migration, proliferation, adhesion and tumorigenesis. Our previous study found that CTEN is a downstream target of p53, a main regulator involved in DNA damage cascade. CTEN protein is reduced with the treatment of cisplatin in human normal prostate epithelial cell line, RWPE-1. In this study, we first hypothesize that CTEN is a target in p53 transduction pathway in response to cisplatin-induced DNA damage. However, our analyses showed that the reduction of CTEN may not be the major factor resulting in proliferative suppression and apoptosis induced by cisplatin in RWPE-1 cells. On the contrary, we found that CTEN expression is induced by cisplatin in human lung cancer cell line A549 and colorectal cancer cell line HCT116. Further analysis of microarray data obtained from Gene Expression Omnibus (GEO) database showed that CTEN expression is up-regulated in a variety of cisplatin-resistant cancer cells compared with parental cells. By analyzing the clinical data from Oncomine database, we also discovered that CTEN expression is relatively higher in cancer types with cisplatin resistance compared with those with cisplatin sensitivity. Therefore, we hypothesize that the upregulation of CTEN may be correlated with cisplatin resistance in cancer cells. By using siRNA-mediated knockdown of CTEN in A549, we found that the reduction of CTEN increases cell viability upon cisplatin treatment, which conflicts with our primary hypothesis. Notably, p21, a cyclin dependent kinase inhibitor, was also reduced in the CTEN knockdown group, which might be the cause of increased cell viability after CTEN knockdown. On the other hand, nuclear CTEN has been demonstrated to interacts with DNA and its binding targets have been identified by ChIP-NGS. We further analyze the potential target genes of CTEN and found that some of them are involved in DNA repair, cell proliferation, cell cycle and apoptosis, which provide possible mechanisms of how CTEN affects cisplatin sensitivity. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T08:21:45Z (GMT). No. of bitstreams: 1 ntu-108-R05b22030-1.pdf: 2141299 bytes, checksum: 745000258b94198de7a9967970b36a61 (MD5) Previous issue date: 2019 | en |
dc.description.tableofcontents | List of Abbreviation iii
摘要 v Abstract vi 1. Introduction: - 1 - 1.1 Cisplatin in cancer therapy - 1 - 1.2 C-terminal tensin like protein and its biological function - 2 - 1.3 The subcellular localizations and associated functions of CTEN - 3 - 1.4 CTEN may be involved in p53 transduction pathway - 4 - 1.5 Aims of this study - 5 - 2. Materials and Methods - 6 - 2.1 Cell Culture - 6 - 2.2 Cell Subculture - 6 - 2.3 Cell counting - 7 - 2.4 Cell proliferation assay - 8 - 2.5 Cell viability assay - 8 - 2.6 siRNA-mediated RNA interference - 8 - 2.7 Plasmid DNA - 9 - 2.8 Plasmid purification - 9 - 2.9 Cell Transfection - 9 - 2.10 Protein analysis - 9 - 2.10.1 Preparation and Quantification of Cell Protein Lysate - 9 - 2.10.2 SDS-PAGE - 10 - 2.10.3 Western Blotting - 10 - 2.11 RNA Analysis - 11 - 2.11.1 Preparation and Quantification of Cell RNA Extract - 11 - 2.11.2 Reverse Transcription - 12 - 2.11.3 Quantitative PCR (q-PCR) - 12 - 2.12 Online Database Searching and Analysis - 13 - 2.13 Analyses of Next Generation Sequencing data - 13 - 3. Results - 15 - 3.1 The reduction of CTEN may not correlate with the proliferative suppression and apoptosis induced by cisplatin. - 15 - 3.2 CTEN is upregulated by cisplatin in colon and lung cancer cells. - 16 - 3.3 The upregulation of CTEN may correlate with cisplatin resistance in cancer cells. - 17 - 3.4 The depletion of CTEN decreases cisplatin sensitivity of A549. - 18 - 3.5 CTEN may affect cell viability upon cisplatin treatment via p21. - 19 - 3.6 ChIP-seq reveals some putative target genes of CTEN that may be involved in modulating cisplatin sensitivity. - 20 - 4. Discussion and Future Perspectives - 22 - 5. References - 26 - 6. Figures and Tables - 34 - | |
dc.language.iso | en | |
dc.title | 探討CTEN蛋白質在cisplatin誘發細胞反應中扮演的角色 | zh_TW |
dc.title | Study on the role of CTEN protein in cellular responses to cisplatin | en |
dc.type | Thesis | |
dc.date.schoolyear | 107-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 莊淳宇(Chun-Yu Chuang),賴韻如(Yun-Ju Lai),謝淑貞(Shu-Chen Hsieh) | |
dc.subject.keyword | 癌症,抗癌藥物,藥物抗性, | zh_TW |
dc.subject.keyword | CTEN,Cancer cell,Cisplatin,DNA repair,Cell cycle,Apoptosis,Cisplatin resistance,Cisplatin sensitivity,DNA binding, | en |
dc.relation.page | 52 | |
dc.identifier.doi | 10.6342/NTU201902950 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2019-08-14 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 生化科技學系 | zh_TW |
顯示於系所單位: | 生化科技學系 |
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