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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 楊淑美 | |
dc.contributor.author | Chia-Hsun Fang | en |
dc.contributor.author | 方嘉勲 | zh_TW |
dc.date.accessioned | 2021-06-07T17:28:23Z | - |
dc.date.copyright | 2020-07-15 | |
dc.date.issued | 2020 | |
dc.date.submitted | 2020-06-05 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/15186 | - |
dc.description.abstract | 如何造成卵巢癌癌幹細胞以及其抗藥性的產生,其致病機轉仍有很多未知的層面存在。在此研究中,我們便是探討酪胺酸激酶c-Kit和細胞膜上的prohibitin (PHB)之間的調控是否會影響卵巢癌幹細胞的表徵以及化療藥物抗性的產生。我們發現c-Kit和PHB蛋白是會共同聚集在細胞膜的脂筏(lipid raft)上,而且與臨床上漿液性卵巢癌的分期是有正相關性的。c-Kit會與PHB連接在一起並促進細胞膜脂筏上的PHB在酪胺酸259的磷酸化,進而增強卵巢癌細胞轉移擴散的能力。我們更進一步將SKOV3帶有GFP和Luciferase螢光蛋白的卵巢癌細胞直接打入小鼠的卵巢,等到其癌細胞擴散到腹腔後再蒐集這些已擴散的癌細胞,重覆幾次後得到擴散轉移能力均較強的SKOV3GL-G4卵巢癌細胞。我們發現SKOV3GL-G4卵巢癌細胞,其c-Kit、Notch3、Oct4、Nanog、SOX2這些幹細胞marker的表現量均有上升的現象。進一步的研究更發現當c-Kit磷酸化細胞膜脂筏上的PHB後,phospho-PHBY259會與Notch3連接在一起,以便穩固Notch3的蛋白不被降解進而增強Notch3的下游PBX1的表現量。降低細胞膜脂筏上PHB蛋白在酪胺酸259的磷酸化,會加速Notch3蛋白被溶酶體分解的降解速率以及去活化β-catenin—ABCG2的訊息傳導途徑。除此之外,我們的實驗也發現細胞膜脂筏上PHB蛋白在酪胺酸259的磷酸化對於卵巢癌的幹細胞特性和對於化療藥物的抗藥性都扮演了很重要的角色。這些包含c-Kit和PHB之間的相互關係,以及細胞膜脂筏上PHB蛋白在酪胺酸259的磷酸化影響Notch3和β-catenin的訊息傳導途徑,進而促進了卵巢癌癌幹細胞和腫瘤的生成都是迄今為止尚未被發現的現象。藉由我們的這項新發現,或許可以透過標靶治療,去抑制c-Kit/raft-phospho-PHBY259的傳導途徑而能有效輔助原本的卵巢癌症療法,減低其復發機率。 | zh_TW |
dc.description.abstract | How does ovarian cancer regulate its stemness and chemoresistance is largely unclear. Here, we explored the role of c-Kit and plasma membrane prohibitin (PHB) in regulating ovarian cancer stemness and chemotherapy resistance. Our results showed that c-Kit and PHB were colocalized and positively correlated in the lipid raft domain of plasma membrane in human ovarian serous carcinoma. Association of c-Kit with PHB and phosphorylated PHB at tyrosine 259 (phospho-PHBY259) in the membrane raft increased ovarian cancer cell migration. Examination of SKOV3GL-G4, a green fluorescent protein and luciferase (GL) labeling metastatic phenotype of SKOV3 ovarian cancer cells generated from xenograft murine ascites, showed a positive correlation between metastatic potential and stem cell characteristics, as indicated by the expression of c-Kit, Notch3, Oct4, Nanog and SOX2. Further study revealed that after activation by c-Kit, raft-phospho-PHBY259 associated with Notch3 to stabilize Notch3 and enhance the downstream target PBX1. Dephosphorylation of raft-PHB at tyrosine 259 degraded Notch3 via a lysosomal pathway and inactivated the β-catenin—ABCG2 signaling. In addition, raft-phospho-PHBY259 played an important role in ovarian cancer stemness and resistance to platinum treatment in vitro and in vivo. These findings disclose a hitherto unreported interrelationship between c-Kit and PHB as well as the involvement of Notch3 and β-catenin signaling pathways in the effects of raft-phospho-PHBY259 on ovarian cancer stemness and tumorigenicity. Targeting the c-Kit/raft-phospho-PHBY259 axis may thus provide a novel therapeutic strategy for treating patients with ovarian cancer. | en |
dc.description.provenance | Made available in DSpace on 2021-06-07T17:28:23Z (GMT). No. of bitstreams: 1 ntu-109-D03642006-1.pdf: 3207685 bytes, checksum: cd1f8f9eb875353d3f4207a53fd80251 (MD5) Previous issue date: 2020 | en |
dc.description.tableofcontents | Table of Contents
謝辭 ................................................................................................................................ I 中文摘要 ...................................................................................................................... II Abstract ........................................................................................................................ III Table of Contents ......................................................................................................... V List of Figures ............................................................................................................. VII List of Tables ............................................................................................................ VIII Abbreviations...............................................................................................................IX Chapter 1. Introduction .............................................................................................. 1 1.1 Overview of ovarian cancer and cancer stem cells (CSCs) ............................ 1 1.2 c-Kit signaling in ovarian cancer .................................................................... 2 1.3 Prohibitin (PHB) ............................................................................................. 3 1.4 Correlation between c-Kit and PHB.................................................................3 1.5 Specific aims.....................................................................................................5 Chapter 2. Materials & Methods ............................................................................... 7 2.1 Drugs ............................................................................................................... 7 2.2 Cells and cell culture ....................................................................................... 7 2.3 Plasmid constructs, reagents and transfection ................................................. 8 2.4 c-Kit siRNA transfection .................................................................................. 9 2.5 In vitro kinase assays and mass spectrum analysis ......................................... 9 2.6 Western blot analysis.......................................................................................11 2.7 Isolation of membrane raft protein..................................................................12 2.8 Immunoprecipitation.......................................................................................13 2.9 Reverse transcription and real-time PCR........................................................13 2.10 Transwell migration assay.............................................................................14 2.11 Cell viability assay .......................................................................................15 2.12 Colony formation assay.................................................................................15 2.13 Spheroid formation assay..............................................................................15 2.14 Fluorescence histochemistry for detection of PHB and c-Kit in the plasma membrane of human ovarian cancer tissues..........................................................16 2.15 Immunofluorescence.....................................................................................17 2.16 In vivo tumor initiation and chemoresistance assay..................................... 18 2.17 Kaplan-Meier curves.....................................................................................19 2.18 Statistical analysis.........................................................................................19 Chapter 3. Results ..................................................................................................... 21 3.1 c-Kit phosphorylates PHB at tyrosine 259 .................................................... 21 3.2 c-Kit and PHB are colocalized and positively correlated in the membrane raft domain of ovarian serous carcinoma .................................................................... 25 3.3 c-Kit-mediated phosphorylation of PHB in the membrane raft enhances cancer cell migration........................................................................................................ 34 3.4 Metastatic phenotypes of SKOV3 show a positive correlation between membrane raft-associated PHB and stem cell characteristics .............................. 38 3.5 c-Kit-mediated phosphorylation of PHB at Y259 in the membrane raft stabilizes Notch3 to activate Notch3—PBX1 signaling ...................................... 44 3.6 c-Kit increases phospho-PHBY259 in the membrane raft to activate β-catenin—ABCG2 signaling ................................................................................................. 51 3.7 Ovarian CSC phenotypes, tumorigenicity and drug resistance require phospho-PHBY259 in the membrane raft ........................................................................ ......53 Chapter 4. Discussion ................................................................................................ 59 References................................................................................................................... 64 List of Figures Figure 1. Group-based Prediction System (GPS) online software predicted that three tyrosine kinases, c-Kit, PDGFR, and EphA3, may phosphorylates PHB at tyrosine 259...................................................................................................................................22 Figure 2. c-Kit phosphorylates PHB at tyrosine 259 by in vitro kinase assay and mass spectrum analysis.............................................................................................................23 Figure 3. Kaplan-Meier curves of overall survival of c-Kit and PHB expression from the KM-Plotter database..................................................................................................27 Figure 4. Colocalization of c-Kit and PHB is positively correlated in the membrane raft domain of ovarian serous carcinoma...............................................................................28 Figure 5. c-Kit phosphorylates PHB in the membrane raft domain to enhance cancer cell motility......................................................................................................................36 Figure 6. Metastatic ovarian cancer cells increase c-Kit, Notch3, and membrane raft-associated PHB and contribute to CSC enrichment........................................................41 Figure 7. c-Kit-mediated raft-phospho-PHBY259 associates with Notch3 to regulate the Notch3—PBX1 signaling pathway..................................................................................47 Figure 8. c-Kit-mediated phospho-PHBY259 in the membrane raft upregulates β-catenin—ABCG2 signaling.............................................................................................52 Figure 9. Raft-phospho-PHBY259 promotes ovarian cancer stem cell survival and potentiates drug-resistant phenotypes..............................................................................55 Figure 10. Downregulation of raft-phospho-PHBY259 suppresses tumorigenic ability and resensitizes tumors to carboplatin treatment...................................................................57 Figure 11. A proposed model to illustrate the mechanism by which c-Kit-mediated phospho-PHBY259 results in subsequent activation of the Notch3 and β-catenin signaling pathways..........................................................................................................................63 List of Tables Table 1. Primer sequences used to amplify specific target genes......................................20 Table 2. Patient specifications of the human ovarian cancer tissue array..........................31 | |
dc.language.iso | en | |
dc.title | 探討酪胺酸激酶c-Kit磷酸化prohibitin對於卵巢癌癌幹細胞與抗藥性所扮演的角色 | zh_TW |
dc.title | Investigation the functional role of c-Kit/phospho-prohibitin in ovarian cancer stemness and chemoresistance | en |
dc.type | Thesis | |
dc.date.schoolyear | 108-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 梁啟銘,蔡孟勳,謝政哲,邱慶豐 | |
dc.subject.keyword | c-Kit,prohibitin,Notch3,β-catenin,癌症幹細胞,細胞膜脂筏, | zh_TW |
dc.subject.keyword | c-Kit,prohibitin,Notch3,β-catenin,cancer stem cells,lipid raft domain of plasma membrane, | en |
dc.relation.page | 73 | |
dc.identifier.doi | 10.6342/NTU202000908 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2020-06-05 | |
dc.contributor.author-college | 生物資源暨農學院 | zh_TW |
dc.contributor.author-dept | 生物科技研究所 | zh_TW |
顯示於系所單位: | 生物科技研究所 |
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