臺灣博碩士論文加值系統

微小核糖核酸為一群大小約為22個核苷酸所組成的小片段非編碼核糖核酸，它被證實具有抑制後轉錄功能進而降低基因表現的能力。微小核糖核酸的生物合成及調控機制在幾乎所有生理及病理的進程中扮演著重要的角色。微小核糖核酸目前已經被發現可以促進或抑制多種癌症中的生長或演進，更進一步也參與在細胞生長的調控及胚胎發展分化的過程中。本研究想探討微小核糖核酸在依賴雌激素生長的乳癌細胞之生長及著床前胚胎發育的分子機轉及重要性。
論文的第一部分，探討雌激素調控的微小核糖核酸在依賴雌激素生長的乳癌進程中所扮演的角色。本研究中發現一個可以被雌激素負向調控的微小核糖核酸miR-34b，藉由負調控cyclin D1及Jag-1而於ER+/p53 wt的乳癌細胞中扮演著抑癌基因的角色。在臨床的乳癌病人中我們發現miR-34b的表現量及ER的表現量呈現負相關性。進一步利用可誘導tet-on系統調控miR-34b表現證實miR-34b可控制乳癌腫瘤及細胞的生長。原位注射過度表現miR-34b乳癌細胞於小鼠乳腺中亦證實miR-34b會影響腫瘤生長。我們進一步驗證了雌激素是藉由影響ER及p53的蛋白質交互作用而非利用附基因(epigenetic) 調控去調控miR-34b。利用環境荷爾蒙diethylstilbestrol及zeranol均具有類似雌激素的作用，即可藉由負向調控miR-34b的表現量而去影響cyclin D1及Jag-1的蛋白質表現。以上的結果有助於對雌激素在乳癌進程中所扮演的角色有更深一層的了解，也證實微小核糖核酸去做為治療標地的新方向。
論文的第二部分，探討以附基因調控研究微小核糖核酸於著床前胚胎發育過程中所扮演的角色。著床前胚胎由morula期到blastocyst期的發育會因5-aza-dC的處理而呈現劑量相關性的抑制(0.01 to 5 μM)，當以低至0.05 贡M的5-aza-dC處理morula 24小時，有將近半數的胚胎仍停留在morula期而無法發育。在處理5-aza-dC後總共有48個微小核糖核酸被負向調控，17個微小核糖核酸被正向調控 (≥5倍差異) 。這些微小核糖核酸包括許多重要的miRNA如let-7e, mir-20a, mir-21, mir-34b, mir-128b, 及mir-452等。我們進一步利用分析軟體及已發表的資料庫去辨識這些微小核糖核酸的預測標靶基因。之後再以即時聚合脢連鎖反應技術(QPCR)去確認這些預測標靶基因是否為真正的標靶。在所有確效的基因中，共發現八個基因 (如dnmt3a 及jag-1)。這些附基因調控的微小核糖核酸及其標靶基因所形成的交互網路並可能在小鼠morula期到blastocyst期胚胎發育中扮演重要的角色。更進一步，這些微小核糖核酸及其標靶基因所提供的線索，有助於吾人進一步了解微小核糖核酸及附基因調控與胚胎發育間的關係。
總而言之，本論文的實驗發現，微小核糖核酸本身不論在乳癌的惡性進程中抑或是胚胎前期的發育中均扮演相當重要的角色。

MicroRNAs (miRNAs) are an evolutionarily conserved class of small non-coding RNAs of approximately 22-nucleotides that decrease gene expression post-transcriptionally. The biogenesis and regulatory machinery of miRNAs play important roles in almost all the physiological and pathological processes. MiRNAs are known to be involved in various kinds of cancers as oncogenes or tumor suppressor genes; and also plays important roles in growth control and embryogenesis. This study addresses whether miRNAs play crucial roles in progressing of estrogen dependent breast cancer cells and development of preimplantation embryos.
The first part of this dissertation aimed to investigate the estrogen regulated miRNAs expression in estrogen dependent breast cancer. We identified one such estrogen down-regulated microRNA, miR-34b, as an onco-suppressor that targets cyclin D1 and JAG-1 in a ER-positive/wild-type p53 breast cancer cell line (MCF-7) as well as in ovarian and endometrial cells, but not in ER-negative or mutant p53 breast cancer cell lines (T47D, MBA-MB-361 and MDA-MB-435). There is a negative association between ER and miR-34b expression levels in ER-positive breast cancer patients. Tet-on induction of miR-34b can cause inhibition of tumor growth and cell proliferation. Also, the overexpression of miR-34b inhibited ER-positive breast tumor growth in an orthotropic mammary fat pad xenograft mouse model. Further validations indicated that estrogen inhibition of miR-34b expression was mediated by interactions between ER and p53, not by DNA methylation regulation. The xenoestrogens diethylstilbestrol and zeranol also showed similar estrogenic effects by inhibiting miR-34b expression and by restoring the protein levels of miR-34b targets, cyclin D1 and JAG-1, in MCF-7 cells. These findings reveal miR-34b as an onco-suppressor microRNA requiring both ER-positive and wild-type p53 phenotypes in breast cancer cells. These results improve our knowledge for developing new therapeutic strategies to target the complex estrogenic pathway in human breast cancer progression through microRNA regulation.
In the second part, the role of epigenetic regulated miRNAs from preimplantation embryos was further studied. Development from morula to blastocyst in mice was dose-dependently inhibited by 5-aza-dC (0.01 to 5 μM), with half of the embryos arrested in morula when treated at levels of 5-aza-dC as low as 0.05 μM. In total, 48 down-regulated microRNAs and 17 up-regulated microRNAs (≥5-fold changes) were identified after 5-aza-dC treatment, including let-7e, mir-20a, mir-21, mir-34b, mir-128b, and mir-452. Their predicted targets were selected based on software analysis and published database. These targets were then validated by Q-PCR, including dnmt3a, and jagged 1 (jag1); overall, at least eight target could be confirmed. These targets are genes possibly controlled by microRNAs that seem to be regulated by 5-aza-dC-induced epigenetic modification and might form an interactive network that regulates morula to blastocyst development. The 5-aza-dC modified microRNA profiles and the identification of the microRNA’s targets during the morula to blastocyst stage in mice provide information that helps us to explore the relationship between fertility, microRNA regulation and epigenetic intervention.
Taken together, the findings of this thesis study suggest that miRNAs alone might be crucial in both breast cancer progression and early embryo development.

Table of Contents

論文電子檔著作權授權書………………………………………………………...
論文審定同意書…………………………………………………………………..
誌謝………………………………………………………………………………. i
中文摘要…………………………………………………………………………... ii
Abstract……………………………………………………………………………. iv
Table of Contents…………………………………………………………………… vi
List of Figures……………………………………………………………………… x
List of Tables……………………………………………………………………… xii
Abbreviations……………………………………………………………………… xiii
Chapter 1 MicroRNA 34b as a Tumor Suppressor in Estrogen-Dependent Growth of Breast Cancer Cells…………………………………………………… 1
Abstract ……………..………………………………………………………….. 2
Introduction ………..……………………………………………………………. 4
Breast cancer ………………………………………………………………. 4
Estrogen receptor signaling…………………………………………………. 5
MicroRNAs …………………………………………………………………. 7
Roles of miRNAs in cancer development and progression…………………. 8
Breast cancer and miRNAs…………………………………………………. 8
Rationale……………………………………………………………………. 10
Hypothesis ………..………………………………………………………. 11
Material and Methods …………………………………………………………. 12
A. Patient specimens ………………………………………………………. 12
B. Cells and treatments……………………………………………………. 12
C. Proliferation assay……………………………………………………. 13
D. Anchorage-dependent colony formation assay…………………………. 13
E. TaqMan Human Low Density (TLDA) MicroRNA Array ……………. 14
F. Quantitative real-time PCR (QPCR) analysis of miRNA expression …. 14
G. Western blots …………………………………………………………. 14
H. Tet-on Vectors and Constructs…………………………………………. 15
I. Stable clone and precursor miRNA transfection………………………. 15
J. Methylation specific PCR and bisulfate sequencing …………………. 16
K. Promoter reporter assay ………………………………………………. 16
L. Luciferase reporter assay ………………………………………………. 17
M. Chromatin immunoprecipitation assay…………………………………. 18
N. The orthotopic mammary fat pad xenograft mouse model……………. 18
O. Immunohistochemistry ………………………………………………. 19
P. Statistical analysis ……………………………………………………. 20
Results …………………………………………………………………………. 21
A. Estrogen-regulated microRNA profile in ER-positive breast cancer cells ……………………………………………………………………. 21
B. Negative correlation of miR-34b expression level and ER status in ER-positive human breast cancers……………………………………. 21
C. Estradiol increased anchorage dependent colony formation and repressed miR-34b expression in MCF-7 cells……………………………………. 22
D. MiR-34b suppressed cell proliferation through directly regulation of Jagged-1 and cyclin D1………………………………………………. 22
E. MiR-34b inhibited tumor growth in mouse mammary fat pad xenografted with MCF-7 pTRE-miR-34b/Tet-on stable clones……………………. 23
F. P53-dependent regulation of miR-34b expression by estradiol……… 24
G. Xenoestrogens and tamoxifen regulates miR-34b expression in breast cancer cells……………………………………………………………. 25
H. MirR-34b/c suppresses cell growth in breast cancer cell lines………. 26
Discussions ……………………………………………………………………. 28
Tables …………………………………………………………………………. 33
Figures …………………………………………………………………………. 38

Chapter 2 MicroRNA regulation via DNA methylation during the morula to blastocyst transition in mice…………………………………………………….. 59
Abstract ……………..………………………………………………………….. 60
Introduction ………..…………………………………………………………. 61
Preimplantation development in mice………………………………………. 61
MicroRNAs in embryo development………………………………………. 62
Epigenetic regulation in embryo development……………………………… 63
Rationale……………………………………………………………………. 64
Material and Methods …………………………………………………………. 65
A. Animal and embryo collection …………………………………………. 65
B. Drug treatment…………………………………………………………. 65
C. Immunofluorescence staining …………………………………………. 65
D. Quantitative real-time PCR (Q-PCR) analysis of miRNA expression … 66
E. SYBR green Real-time quantitative RT-PCR …………………………. 66
F. miRNA targets prediction ……………………………………………. 67
G. Statistical analysis ……………………………………………………. 67
Results …………………………………………………………………………. 69
A. Inhibition of DNA methylation by 5-aza deoxycytidine is able to alter early embryo development ……………………………………………. 69
B. Effects of 5-aza-dC-induced arrested development on miRNA expression profile…………………………………………………………………. 69
C. Target prediction and validation of the 5-aza-dC regulated miRNAs………………………………………………………………. 70
Discussions ……………………………………………………………………. 72
Tables …………………………………………………………………………. 79
Figures …………………………………………………………………………. 84
References ………………………………………………………………………. 93
Plasmid maps …………………………………………………………………. 113
Appendices ……………………………………………………………………… 119

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