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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林淑華 | |
dc.contributor.author | Ching-Tzu Yen | en |
dc.contributor.author | 顏靜慈 | zh_TW |
dc.date.accessioned | 2021-05-14T17:44:42Z | - |
dc.date.available | 2021-02-26 | |
dc.date.available | 2021-05-14T17:44:42Z | - |
dc.date.copyright | 2016-02-26 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-11-10 | |
dc.identifier.citation | 第一部分
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Kawase Y, Ly HQ, Prunier F, Lebeche D, Shi Y, Jin H, et al. Reversal of cardiac dysfunction after long-term expression of SERCA2a by gene transfer in a pre-clinical model of heart failure. Journal of the American College of Cardiology 2008 Mar 18; 51(11): 1112-1119. 36. Jessup M, Greenberg B, Mancini D, Cappola T, Pauly DF, Jaski B, et al. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure. Circulation 2011 Jul 19; 124(3): 304-313. 37. Wahlquist C, Jeong D, Rojas-Munoz A, Kho C, Lee A, Mitsuyama S, et al. Inhibition of miR-25 improves cardiac contractility in the failing heart. Nature 2014 Apr 24; 508(7497): 531-535. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/4653 | - |
dc.description.abstract | 第一部分:
急性淋巴性白血病為最常見的兒童癌症,而造成 ETV6/RUNX1 融合基因表現的 t(12;21) 染色體轉位則是在兒童急性前 B 細胞淋巴性白血病中最常見的染色體異常。微核醣核酸是一非編碼的小核醣核酸,長度僅 18–23 個核苷酸,是由 70-100 個核苷酸的微核醣核酸前驅物切割而來,其作用主要是在後基因轉錄階段抑制基因表達。幾乎所有的生理機制都受到微核醣核酸的影響,包括造血細胞分化,甚至已知有部分微核醣核酸參與在白血病癌化過程中。為探討與 ETV6/RUNX1 相關之微核醣核酸,本研究分析 50 個兒童前 B 細胞淋巴性白血病檢體中微核醣核酸的表達情形,其中包含 10 個 ETV6/RUNX1 陽性病例。透過與 ETV6/RUNX1 陰性病人細胞相比較,本研究找到 17 個在 ETV6/RUNX1 陽性病人細胞表達量顯著下降的微核醣核酸。在這些具顯著差異的微核醣核酸之中,由微核醣核酸 181a-1 前驅物 3ʹ 端衍生而來的成熟產物微核醣核酸 181a-1(miR-181a-1),其表現量的改變最具統計意義(下降近百分之七十五,P值 < 0.001)。此外,MIR181A1 基因中具有 RUNX1 蛋白的 DNA 結合位(TGTGGT),因此本研究選擇針對 MIR181A1 進行更深入的探討。 REH 細胞為 ETV6/RUNX1 陽性的前B細胞急性淋巴性白血病細胞株,本研究利用小片段干擾 RNA 抑制 REH 細胞的 ETV6/RUNX1 表達可使 miR-181a-1 表現量上升,此外在人類胚胎腎臟 293FT 細胞中過量表達 ETV6/RUNX1 融合蛋白則可抑制 miR-181a-1 表現量。本研究並以免疫染色質沉澱法(chromatin immunoprecipitation)在 REH 細胞株驗證被預測的 RUNX1 結合位,證明 MIR181A1 直接受到 ETV6/RUNX1 融合蛋白調控。相較於 miR-181a-1,被報導具有功能的是另一股微核醣核酸 181a(miR-181a),為尋找其下游標的,本研究將 REH 細胞轉染 miR-181a 並檢測 PLAG1 表達,已知在慢性淋巴性白血病(chronic lymphoblastic leukemia)中 PLAG1 為 miR-181a 標的。在過量表達 miR-181a 的 REH 細胞中,PLAG1 蛋白表達量下降;而在 ETV6/RUNX1 陽性臨床檢體中 PLAG1 mRNA 表達明顯增加。上述證據皆指出,如同慢性淋巴性白血病研究結果,PLAG1 基因在兒童急性淋巴性白血病亦為 miR-181a 標的。此外,在 miR-181a 轉染之 REH 細胞中 ETV6/RUNX1 蛋白表達量亦顯著下降,且與 RUNX1 3ʹ 端未轉譯區域(3ʹ -untranslated region)上的 miR-181a 辨識序列(UGAAUGU)相關。本研究並利用 REH 細胞證明過量表達 miR-181a 會促進表現 ETV6/RUNX1 之前 B 細胞急性淋巴性白血病細胞由前 BI 階段(pre-BI stage)分化為未成熟 B 細胞(immature B cells)。且 miR-181a 亦可誘導 ETV6/RUNX1 陽性臨床病人檢體 CD10 抗原表達量減少,意即細胞有部分分化的現象。 統整上述研究成果,本研究顯示 MIR181A1 及 ETV6/RUNX1 可相互調控,並推論一涉及 MIR181A1 與 ETV6/RUNX1 的雙向負調控迴圈機制可能參與在由 ETV6/RUNX1 驅動之前B細胞急性淋巴性白血病分化停滯。 第二部分: 微核醣核酸在後轉錄階段可藉由負向調控編碼基因的表現,影響細胞的各種生理層面。目前已知微核醣核酸151會與宿主基因PTK2一起表達,在先前研究中則顯示微核醣核酸151與癌症及心臟肥大症相關,但整體來說,關於微核醣核酸151的報導相當少。儘管已有數個目標基因被發表,包括RhoGDIA、CCNE1、和 ATP2A2基因,微核醣核酸151的生理功能及病理角色仍不清楚。先前針對60個兒童急性淋巴性白血病檢體分析微核醣核酸表達,發現微核醣核酸151在前 B 細胞急性淋巴性白血病中表現量遠高於T細胞急性淋巴性白血病,為了解微核醣核酸151在此現象中扮演的角色,本研究利用基因重組工程技術產製微核醣核酸151 (Mir151)基因剔除小鼠並已確認在DNA及RNA表現上皆為Mir151缺失。本研究並進一步探討Mir151基因剔除鼠的表現型,發現年輕小鼠(小於1歲)的紅血球生成增加並伴隨腎臟紅血球生成素轉錄的上升,此現象在缺氧環境下更為顯著且可能與Hif-α的調控機制相關。在長期觀測結果中,我們發現Mir151缺失並未影響長期存活,但年紀較長的小鼠(大於1.5歲)中,有33% Mir151+/- 及23% Mir151-/-小鼠產生自發性肺癌。本研究並更進一步利用urethane在年輕小鼠誘導肺癌產生,結果卻與預期不同,Mir151 缺乏在年輕小鼠身上具有保護作用。 統整上述結果,本研究揭露了微核醣核酸151先前未被發現的生理及病理角色,並為之後的研究提供新的研究方向。 | zh_TW |
dc.description.abstract | The first part:
Acute lymphoblastic leukemia is the most common pediatric cancer, and the chromosomal translocation t(12;21), which resulting in expression of ETV6/RUNX1 fusion gene, is the most frequent chromosomal lesion in childhood B-cell precursor (pre-B) ALL. MicroRNAs (miRNAs) are small noncoding RNAs with 18–23 nucleotides arisen from cleavage of 70-100 nucleotide precursors and mostly down regulate gene expression at post-transcriptional level. They have been implicated in virtually all aspects of biology including hematopoietic cell differentiation and some of them are also known to participate in leukemogenesis. To investigate the miRNAs that are associated with regulation of ETV6/RUNX1 expression, we performed miRNA expression profiling on fifty leukemic samples from children with pre-BALL, including 10 cases positive for ETV6/RUNX1. We identified 17 miRNAs that were down-regulated in ETV6/RUNX1-positive, compared with ETV6/RUNX1-negative B-ALL. Of these miRNAs, miR-181a-1, one of the mature form derived from the 3ʹ arm of precursor hsa-mir-181a-1, gives the most significant fold-change (reduced by ~75%, P<0.001). In addition, MIR181A1 contains a potential RUNX1 binding site (TGTGGT), thus we selected MIR181A1 for further investigation. In REH cells, an ETV6/RUNX1-positive B-ALL line, siRNA knockdown of ETV6/RUNX1 resulted in increased miR-181a-1 expression, while overexpression of ETV6/RUNX1 fusion protein in HEK-293FT cells resulted in reduction of miR-181a-1 level. The predicted RUNX1 binding site was also confirmed in REH cells by chromatin immunoprecipitation analysis, indicating MIR181A1 is a direct target of the ETV6/RUNX1 fusion protein. To search for downstream targets of miR-181a, the functional counterpart of miR-181a-1, REH cells were transfected with miR-181a and the expression of PLAG1, shown to be a target of miR-181a-1 in chronic lymphoblastic leukemia (CLL) was examined. The PLAG1 protein level was decreased in miR-181a over-expressed REH cells. In addition, the PLAG1 mRNA level was increased in ETV6/RUNX1-positive clinical samples. This indicated that PLAG1 gene might be the down-stream target of miR-181a in childhood ALL as in CLL. Furthermore, we found ETV6/RUNX1 protein was also decreased in miR-181a-transfected REH cells, correlating with the existence of a miR-181a recognition sequence (UGAAUGU) at the 3’-untranslated region of RUNX1. Using REH cells, we showed ectopic expression of miR-181a could enhance ETV6/RUNX1-expressing B-ALL cells differentiate from pre-BI stage to immature B cells. In addition, miR-181a could induce partial differentiation of ETV6/RUNX1-positive clinical patient samples by diminishing CD10 expression. Taken together, our results demonstrate that MIR181A1 and ETV6/RUNX1 regulate each other, and we propose that a double negative loop involving MIR181A1 and ETV6/RUNX1 may contribute to ETV6/RUNX1-driven differentiation arrest in B-ALL. The second part: MicroRNAs (miRNAs) are the major key players to negatively regulate the expression of coding genes in post-transcriptional level and control almost all aspects of biology of the cells. MIR151A expresses a miRNA that co-expresses with PTK2 gene and has been reported to be involved in cancers and cardiac hypertrophy. The description about MIR151A in previous reports is rare. Although several target mRNAs including RhoGDIA, CCNE1, and ATP2A2 have been identified, the physiological function and pathological role of MIR151A1 remains a puzzle. We have performed a miRNA expression profiling on 60 childhood ALL patients and identified miR-151 to be differentially expressed in B-ALL. To elucidate the role of miR-151 involved in this phenomenon, we generated and the Mir151 conventional knockout mice using recombineering technology and confirmed the deficiency of Mir151 gene on both DNA and RNA level. We further characterized phenotypes of Mir151 knockout mice and found in young mice (< 1year) an increased erythropoiesis concordant with the elevated renal Epo transcription, which was more prominent under hypoxic and may associate with a Hif-α-regulated mechanism. In elder mice (>1.5 year), we found that Mir151 deficiency did not affect the long-term survival, whereas spontaneous lung tumors were developed in 33% Mir151+/- and 23% Mir151-/- mice. We further performed a urethane-induced lung cancer model on young N10F2 mice, however, an unexpected protective effect of was exerted in young mice deficient in Mir151. Taken together, our results reveal the undiscovered physiological and pathological role of MIR151A, which may provide new aspects for future research. | en |
dc.description.provenance | Made available in DSpace on 2021-05-14T17:44:42Z (GMT). No. of bitstreams: 1 ntu-104-D98424003-1.pdf: 9783098 bytes, checksum: 2b58fbf7892600d2da7ec3452e6159a3 (MD5) Previous issue date: 2015 | en |
dc.description.tableofcontents | Table of Contents
前言 I Preface II 誌謝 III Abbreviation IV Table of content VII 'The First Part of Childhood Acute Lymphoblastic Leukemia Associated MicroRNAs: I. A Double Negative Loop Comprising of ETV6/RUNX1 and MIR181A1' 1 摘要 2 Abstract 4 List of Figures 7 List of Tables 9 List of Appendixes 10 Chapter 1. Introduction 11 1.1. Childhood B-cell precursor acute lymphoblastic leukemia 11 1.2. Genetic aberrations in B-ALL 11 1.3. ETV6/RUNX1-positive B-ALL 13 1.3.1. ETV6/RUNX1 fusion gene 13 1.3.2. Structure and function of ETV6/RUNX1 fusion protein 14 1.3.3. Role of ETV6/RUNX1 in leukemogenesis of B-ALL 15 1.4. MicroRNAs 16 1.4.1. Overview 16 1.4.2. MicroRNAs in hematopoiesis and leukemogenesis 17 1.4.3. MIR181A1 gene 18 1.4.4. MicroRNAs associated with ETV6/RUNX1 19 1.5. Research motive and the aim 20 Chapter 2. Materials and Methods 21 2.1. Materials 21 2.1.1. Reagents 21 2.1.2. Kits 22 2.1.3. Antibodies 23 2.1.4. Vectors 24 2.1.5. Instruments 24 2.2. Methods 25 2.2.1. Patients 25 2.2.2. RNA preparation 26 2.2.3. Quantitative real-time PCR 26 2.2.4. MicroRNA expression profile 27 2.2.5. Cell culture 27 2.2.6. Cell viability 28 2.2.7. Proliferation and cell cycle 28 2.2.8. Apoptosis assay 29 2.2.9. Flow cytometric analysis of lineage markers 30 2.2.10. Chromatin immunoprecipitation 30 2.2.11. Western blotting 31 2.2.12. siRNA transfection 31 2.2.13. miRNA precursor transfection 32 2.2.14. ETV6/RUNX1 and RUNX1 protein overexpression 32 2.2.15. Lentiviral construct and infection 33 2.2.16. Luciferase reporter assay 34 2.2.17. Statistical analyses 34 Chapter 3. Results 36 3.1. ETV6/RUNX1 directly downregulates MIR181A1 36 '3.1.1 ETV6/RUNX1-associated miRNA expressions in clinical samples' 36 '3.1.2 siRNA knockdown of ETV6/RUNX1 up-regulates miR-181a-1 expression' 37 '3.1.3 Overexpression of ETV6/RUNX1 down-regulates miR-181a-1 expression' 38 3.1.4 ETV6/RUNX1 binds the regulatory region of MIR181A1 39 '3.1.5 Transcriptional co-repressor HDAC3 is recruited to the regulatory region of MIR181A1 ' 39 3.2. MIR181A1 targets PLAG1 oncogene in B-ALL 40 3.2.1. Upregulation of PLAG1 mRNA in clinical samples 40 '3.2.2. Overexpression of miR-181a inhibits PLAG1 expression in REH cells' 41 3.3. MIR181A1 negatively regulates ETV6/RUNX1 42 '3.3.1. Overexpression of miR-181a downregulates ETV6/RUNX1 in REH cells' 42 '3.3.2. miR-181a targets the miR-181a recognition sequence located in RUNX1-3' UTR' 42 3.4. The cellular effects of MIR181A1 on B-ALL cells 43 3.4.1. Ectopic expression of MIR181A1 impedes REH cell growth 43 '3.4.2. Apoptotic cells increases in MIR181A1-lentivirus transduced REH cells' 44 '3.4.3. The percentage of G0/G1 phase population increases in MIR181A1-lentivirus transduced REH cells' 44 '3.4.4. Ectopic expression of MIR181A1 enhances REH cell differentiation ' 45 '3.4.5. MIR181A1 expression enhances apoptosis of differentiated cells' 45 '3.4.6. Ectopic expression of MIR181A1 induces partial differentiation of ETV6/RUNX1-positive primary ALL blasts' 46 Chapter 4. Discussion 48 4.1 Selection of Mir181A1 to be investigated 48 4.2 The relationship between ETV6/RUNX1 and MIR181A1 49 4.3 A double negative loop comprising ETV6/RUNX1 and MIR181A1 51 4.4 The effects of MIR181A1 on B-ALL cells 52 Chapter 5. Conclusion and Prospective 55 Bibliography 57 Figures 68 Tables 104 Appendixes 110 'The Second Part of Childhood Acute Lymphoblastic Leukemia Associated MicroRNAs: II. Establishment of Mir151 conventional knockout mice' 116 摘要 117 Abstract 118 List of Figures 120 List of Tables 121 List of Appendixes 122 Chapter 6. Introduction 123 6.1. MicroRNAs 123 6.2. microRNA 151a 124 6.2.1. Human MIR151A gene 124 6.2.2. Clinical association and target mRNAs of MIR151A 125 6.2.3. Mouse Mir151 gene 126 6.3. Research motive and the strategy 126 Chapter 7. Materials and Methods 128 7.1. Materials 128 7.1.1. Reagents 128 7.1.2. Kits 129 7.1.3. Vectors 129 7.1.4. Equipment 129 7.2. Methods 130 7.2.1. Targeting vector construction 130 '7.2.2. Gene targeting of ES cells and generation of Mir151 conventional knockout (KO) mice' 131 7.2.3. Animals 132 7.2.4. RNA preparation and reverse transcription 133 7.2.5. Quantitative real-time PCR 133 7.2.6. Complete blood counts and differential counts 134 7.2.7. Clinical chemistry 134 7.2.8. Chronic hypoxia 135 7.2.9. CoCl2 treatment 135 7.2.10. Tumor analysis 136 7.2.11. Urethane-induced lung cancer model 136 7.2.12. Histological analysis 137 7.2.13. Statistical analyses 137 Chapter 8. Results 138 8.1. Generation and identification of Mir151 conventional knockout mice 138 8.1.1 Generation of Mir151 conventional knockout mice 138 8.1.2 Identification of gene status in DNA and RNA level 138 8.2. Characterization of Mir151 conventional knockout mice 139 8.2.1 Mir151 is not essential to survival 139 8.2.2 A kinetic change of erythropoiesis 140 8.2.3 Elevated renal Epo mRNA level in young MiR151-/- mice 140 8.2.4 Induction of renal Epo by chronic hypoxia 141 8.2.5 No increase in renal Epo-producing cells in MiR151-/- mice 142 8.2.6 Increase of Hif-α target gene expressions in young MiR151-/- mice 143 8.2.7 Induction of Epo expression by CoCl2 treatment 144 8.3. Long-term observation of Mir151 conventional knockout mice 144 8.3.1 No difference in survival 144 8.3.2 Spontaneous developed lung cancer in elder Mir151 knockout mice 145 '8.3.3. Increase number of urethane-induced lung tumors in elder Mir151 knockout mice' 145 '8.4. Depletion of Mir151 protected young mice from urethane-induced lung cancer' 146 Chapter 9. Discussion 147 9.1. Increased erythropoiesis in young mice 147 '9.2. Spontaneous developed and urethane-induced lung cancer in elder mice v.s. the protective effect of Mir151 loss in young mice.' 148 9.3. The potential application of Mir151 knockout mice 149 Chapter 10. Conclusion and Prospective 150 Bibliography 151 Figures 155 Tables 175 Appendixes 180 | |
dc.language.iso | en | |
dc.title | 探討兒童急性淋巴性白血病相關之微核醣核酸-181A及微核醣核酸-151的功能 | zh_TW |
dc.title | Investigating the function of childhood acute lymphoblastic leukemia associated microRNAs: miR-181A and miR-151 | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 林淑容,俞松良,楊性芳,林東燦,曾慶平 | |
dc.subject.keyword | 前B細胞急性淋巴性白血病,t(12;21)轉位,ETV6/RUNX1,微核醣核酸 181a-1,微核醣核酸 181a,微核醣核酸 151,基因剔除小鼠,紅血球生成素,慢性缺氧,自發性肺癌, | zh_TW |
dc.subject.keyword | pre-B ALL,t(12;21) translocation,ETV6/RUNX1,miR-181a-1,miR-181a,miR-151,genetic knockout mice,erythropoietin,chronic hypoxia,spontaneous developed lung cancer, | en |
dc.relation.page | 184 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2015-11-11 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
顯示於系所單位: | 醫學檢驗暨生物技術學系 |
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