系統識別號 U0026-0406201316133500
論文名稱(中文) 篩選特異miRNAs與aptamers為癌幹細胞之標靶以偵測與治療癌症
論文名稱(英文) Identification of miRNAs/aptamers targeting cancer stem cell for cancer detection and therapy
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 101
學期 2
出版年 102
研究生(中文) 謝宜珊
研究生(英文) I-Shan Hsieh
學號 s58961141
學位類別 博士
語文別 英文
論文頁數 100頁
口試委員 指導教授-陳玉玲
中文關鍵字 癌幹細胞  微小核醣核酸  適體 
英文關鍵字 Cancer stem cell  miRNA  Aptamer 
中文摘要 癌幹細胞又稱腫瘤起源細胞,目前所知在癌細胞中占極少數的比例,因具有自我更新及分化的特性,可驅使腫瘤的形成以及增加癌轉移與對藥物治療產生抗藥性。因此,發展合成的短小寡核酸,如: microRNAs, small interfering RNA以及aptamers對於癌幹細胞的偵測與治療為一個理想的方向。本篇論文主要涵蓋兩個主題,在第一個研究主題中,我們發現miR-320的表現量在前列腺癌腫瘤組織中較非腫瘤組織表現量相對減少。將miR-320過度表現於前列癌細胞株,在體內與體外試驗中皆顯示可抑制腫瘤的生成。miR-320經由透過3’UTR抑制β-catenin的表現,而miR-320的減少,在癌幹細胞樣細胞以及臨床檢體中,會增進β-catenin的表現。我們更進一步證實,減少miR-320的表現量,在前列腺癌與肺癌細胞株中會誘導癌幹細胞之特性,使癌細胞株具有高度的自我更新、抗藥性與癌化的能力。此外,我們更發現將癌幹細胞樣細胞過度表現miR-320,會抑制前列腺癌以及肺癌其癌幹細胞樣細胞的特性。這些結果證實miR-320經由負調控Wnt/β-catenin pathway扮演抑癌基因的角色,在未來對於前列腺癌的偵測與診斷也是重要的標的基因。在第二個研究主題,為了尋找可以專一性結合於癌幹細胞的aptamer,我們以Cell-SELEX篩選出一條對於對癌幹細胞樣細胞具有特異性的DNA aptamer,命名為AP-9R。在體外試驗中,相較於一般癌細胞以及正常細胞,AP-9R更能夠特異性的辨識癌幹細胞樣細胞,並且具有高度的結合力。同時,我們也證實AP-9R不具有細胞毒性並且能有效的抑制癌幹細胞樣細胞的爬行能力,這些作用或許是透過一個在癌幹細胞會高度表現的目標蛋白Annexin A2。研究結果顯示,AP-9R可發展作為偵測癌幹細胞的生物標誌,在應用於癌症的治療方面也具有可行性。
英文摘要 Cancer stem cells (CSC), also called tumor initiating cells (TIC), are a small population of cancer cells within a tumor that drive the tumor initiation, metastasis, and resistance to chemotherapeutic drugs. An effective cancer stem cell targeting strategy by oligonucleotide-based approaches, including microRNAs, small interfering RNAs and aptamers in diagnosis and treatment are urgently needed. This dissertation is composed of two main parts. In the first part, we report findings that miR-320 is significantly downregulated in prostate cancer (PCa). Overexpression of miR-320 in PCa cells decreases PCa tumorigenesis in vitro and in vivo. MicroRNA-320 inhibits β-catenin expression by targeting the 3′-untranslated region of β-catenin mRNA. The reduction of miR-320 resulting in increased β-catenin was also found in prostate CSCs and clinical PCa specimens. Interestingly, knockdown of miR-320 significantly increases the cancer stem cell properties, such as tumorsphere formation, chemoresistance, and tumorigenic ability. Furthermore, increased miR-320 expression in prostate and lung CSCs significantly suppresses cancer stem cell properties of PCa and lung cells. These results suggest that miR-320 is a key negative regulator in CSCs, and suggest that developing miR-320 as a novel therapeutic agent may offer benefits for cancer treatment. In the second part, we aimed to develop an effective aptamer-based biomarker for CSCs in cancer therapy. We isolated DNA aptamers with high affinity to CSCs by Cell-SELEX. The aptamer AP-9R bound to lung CSCs, but did not bind with normal cells. In addition, AP-9R blocked cell migration and exhibited no apparent cytotoxicity in vitro. Using mass spectrometry identification and flow cytometry confirmation, the target protein of AP-9R was characterized to be Annexin A2, which was highly expressed in non-small cell lung cancer. Moreover, AP-9R mediated blocking of Annexin A2 reduces migration of lung CSCs. Taken together, our data indicate that both miRNA-based and aptamer-based therapies will be useful as therapeutic and diagnostic agents for CSCs.
論文目次 Abstract in Chinese I
Acknowledgements IV
Contents VI
Table contents IX
Figure contents X
Abbreviation XII
Chapter1. Introduction 1
1. General introduction of cancer stem cells 1
2. Epithelial-mesenchymal transition in cancer stem cells 2
3. General introduction of miRNAs 3
4. miRNA Biogenesis and Functions 4
5. miRNA in cancer and cancer stem cells 5
6. General introduction of Aptamer 5
7. Microfluidic-Based SELEX 6
8. Cell-SELEX 7
9. Annexin A2 as a cancer antigen 8
Objectives of study 10
Chapter 2.Materials and methods 11
Part 1. To investigate the cancer stem cells related miRNAs 11
Clinical tissues and cell lines 11
Collecting miR-320 expression datasets 11
Quantitative RT-PCR 12
Cell transfection and Western blotting 12
Cell proliferation and soft-agar colony formation assays 13
Microarray analysis and pathway analysis 13
MicroRNA reporter assays 14
In situ hybridization (ISH) and immunohistochemistry 14
Immunofluorescence staining 15
TOP-/FOP-FLASH Wnt reporter assay 15
Lentivirus production and infection 15
Sphere formation assay 16
Colony formation assay 17
Cytotoxicity Assay 17
Tumorigenicity assays in NOD/SCID mice 17
Flow cytometric analysis 17
Magnetic cell sorting 18
Part 2. Selection of cancer stem like cell-specific aptamers. 18
Cell lines 18
Library preparation and reagents for SELEX 19
Aptamer binding assay 19
Flow cytometric analysis 20
Confocal fluorescence imaging 20
Capture assay 20
Cytotoxicity Assay 20
Migration Assays 21
Identification of the protein target of AP-9R 21
Pull-Down Assay 21
Chaprer 3. Results 23
Part 1. To investigate the cancer stem cells related miRNAs 23
Downregulation of MiR-320 in PCa. 23
MiR-320 directly inhibits β-catenin expression via its 3-UTR. 24
MiR-320 levels inversely correlate with β-catenin protein levels in PCa. 25
MiR-320 inhibits β-catenin/T-cell factor (TCF)-mediated transcription and decreases cell viability and anchorage-independent proliferation. 25
cDNA microarray revealed that Wnt pathway and stem cell markers could be regulated by miR-320 27
MicroRNA-320 is downregulated in cancer stem-like cells and overexpression of miR-320 inhibits stem cell-like properties 28
Downregulation of miR-320 promotes cancer stem cell- like properties 30
Part 2: Selection of Cancer stem like cell-specific aptamers. 31
Identification of cancer stem cell specific DNA Aptamers with the Cell-SELEX Method 31
Targeting the lung cancer stem like cells with aptamer AP-9R 32
Investigation of the biological function of AP-9R 33
To identify the AP-9R protein target 33
Chapter 4. Discussion 35
Chapter 5. Conclusion 44
References 45
Tables 54
Figures 59
Appendix 94
Equipments 97
Curriculum Vitae 99
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