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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 楊志新(James Chih-Hsin Yang) | |
dc.contributor.author | Pei-Shan Hung | en |
dc.contributor.author | 洪珮珊 | zh_TW |
dc.date.accessioned | 2021-06-16T08:15:35Z | - |
dc.date.available | 2020-08-26 | |
dc.date.copyright | 2020-08-26 | |
dc.date.issued | 2020 | |
dc.date.submitted | 2020-07-13 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/58450 | - |
dc.description.abstract | KRAS基因變異而導致癌症的發生約佔30% ,特別是發生在胰臟癌、大腸癌、肺癌等這些高度惡性癌症。針對KRAS基因突變的治療標的是有相當的困難度。KRAS的基因變異主要為錯義突變(missense mutation),其中,在胺基酸12、13和61的密碼子是突變的熱點。KRAS的錯義突變,會提高抵抗GTPase activating protein (GAP) 所引起的 GTP 水解能力,與降低內生性GTP 水解能力,進而導致RAS-GTP鎖定在活化狀態之下,且持續活化下游訊息傳遞。近來許多文獻指出,KRAS基因的突變亞型,並不能被視為同一種基因突變。然而,卻缺乏對於各別KRAS基因突變亞型的特性,與相關致癌機制的研究與探討。在本論文裡,我們驗證在非小細胞肺癌中,KRAS基因突變亞型KRASG12V 與 KRASG12D所引起的癌症轉移機轉差異,並且使用Wnt/β-catenin pathway 抑制劑可以降低KRASG12V所引起的非小細胞肺癌細胞轉移。 我們使用H838等基因系細胞株 (isogenic cell line),以排除癌細胞內基因背景的干擾。首先,我們發現KRASG12V 與KRASG12D,在細胞實驗 (in vitro) and與動物實驗 (in vivo) 中,觀察到不同的轉移 (metastasis) 能力。透過基因集(GSEA)的分析後,在H838KRASG12V細胞所表現的基因集與RhoA-related signaling基因集相比,比對結果呈現負相關。我們也進一步發現,在H838KRASG12D細胞中,KRASG12D反而引起較高的RhoA活性,且具有較低的Wnt/β-catenin 活化。當抑制H838KRASG12D細胞內的RhoA活性後,則可以偵測到提高的Wnt/β-catenin 的活化。此外,當給予Wnt/β-catenin抑制劑後,可降低H838KRASG12V細胞的爬行 (migration) 能力。在本論文,我們闡明了在KRAS 所引起的非小細胞肺癌裡,KRAS/RhoA/Wnt/β-catenin所調控的轉移機轉。KRASG12V所引起的轉移對於Wnt/β-catenin機制有較高的依賴。我們的研究結果證實,KRASG12V 與KRASG12D基因變異亞型所引起的非小細胞肺癌轉移,在設計治療方法上,應被視為獨立的疾病 | zh_TW |
dc.description.abstract | The KRAS mutations has been an obstacle to identify therapeutic targets in cancer treatment. In this work, we clarified the distinct metastasis pattern of Non-Small-Cell Lung Carcinoma (NSCLC) induced by KRASG12V/KRASG12D mutations and inhibited the KRASG12V mediated metastasis by Wnt inhibitor. First, we found that KRASG12V induced more aggressive phenotype in Vitro and in Vivo experiments. The Gene Set Enrichment Analysis (GSEA) results of H838 KRASG12V cells showed a significant negative correlation with RhoA-related signaling. Following this clue, we observed KRASG12D induced higher activation of RhoA and suppressed activation of Wnt/β-catenin in H838 KRASG12D cells. The restored activation of Wnt/β-catenin in H838KRASG12D cells could be detected when expression with a dominant-negative mutant of RhoA or treatment with RhoA inhibitor. Furthermore, the Wnt inhibitor abolished the KRASG12V -induced migration. We elucidated the importance of the axis of RhoA/Wnt in regulatory NSCLC metastasis driven by KRAS mutations. Our data indicate that KRASG12V driven NSCLC metastasis is Wnt-dependent and the mechanisms of NSCLC metastasis induced by KRASG12V/KRASG12D is distinct. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T08:15:35Z (GMT). No. of bitstreams: 1 U0001-1307202015494900.pdf: 9638464 bytes, checksum: db03d81c3e7b1f11f9f213d8bfcf72ac (MD5) Previous issue date: 2020 | en |
dc.description.tableofcontents | Contents 誌謝 ⅰ 中文摘要 ⅱ Abstract ⅳ Abbreviation ⅴ Contents ⅵ List of Figures ⅸ List of Tables xi Highlights xii ChapterⅠ- Overview the background and Rationale 1 1. Lung cancer 1 1.1 Significance of lung cancer worldwide and in Taiwan 1 1.2 The histological classification of lung cancer 1 1.3 The risk factors and lung cancer 1 2. The KRAS mutation in Lung caner 4 2.1 The background of Ras 4 2.2 KRAS act as a driver of tumorigenesis in NSCLC 5 2.3 KRAS in cancer therapy 6 3. The plasticity of cells 7 3.1 The plasticity of cells– EMT 7 3.2 The plasticity of cells – Rho family GTPase 8 4. The signaling pathway of Wnt/β-catenin 10 4.1 The canonical pathway of Wnt/β-catenin 10 4.2 The canonical pathway of Wnt/β-catenin in cancer 11 4.3 The canonical pathway of Wnt/β-catenin in NSCLC 13 5. Hypothesis of the current thesis 14 Chapter Ⅱ- Different KRAS mutation subtypes cause distinct cell morphologies and characteristics 15 1. Introduction 15 2. Materials and Methods 15 3. Results 23 4. Discussion 27 Chapter Ⅲ- The axis of RhoA and Wnt/β-catenin in NSCLC metastasis elicited by KRASG12V and KRASG12D mutations 29 1. Introduction 29 2. Materials and Methods 29 3. Results 34 4. Discussion 37 Chapter Ⅳ- The mutation of KRASG12V promote metastasis through Wnt/β-catenin pathway 40 1. Introduction 40 2. Materials and Methods 41 3. Results 44 4. Discussion 45 Figures 46 Tables 74 Reference 76 Appendices 85 | |
dc.language.iso | en | |
dc.title | 阻斷WNT訊息傳導以遏制KRAS引起肺癌轉移 | zh_TW |
dc.title | The Inhibition of Wnt Restrain KRASG12V-Driven Metastasis in Non-Small-Cell Lung Cancer | en |
dc.type | Thesis | |
dc.date.schoolyear | 108-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 郭頌鑫(Sung-Hsin Kuo),施金元(Jin-Yuan Shih),趙祖怡(Tsu-Yi Chao),楊慕華(Muh-Hwa Yang),徐志宏(Chih-Hung Hsu) | |
dc.subject.keyword | 癌症轉移,非小細胞肺癌,KRASG12D基因,KRASG12V基因,Wnt/β-catenin 活化,RhoA基因, | zh_TW |
dc.subject.keyword | metastasis,NSCLC,KRASG12D,KRASG12V,RhoA,Wnt/β-catenin, | en |
dc.relation.page | 85 | |
dc.identifier.doi | 10.6342/NTU202001474 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2020-07-14 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 腫瘤醫學研究所 | zh_TW |
顯示於系所單位: | 腫瘤醫學研究所 |
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