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博碩士論文 etd-0728114-162835 詳細資訊
Title page for etd-0728114-162835
論文名稱
Title
利用次世代定序在口腔癌全面性微型核糖核酸之分析
Next Generation Sequencing for Comprehensive Analysis of MicroRNA Profiles in Oral Cancer
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
85
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2014-07-04
繳交日期
Date of Submission
2014-08-28
關鍵字
Keywords
口腔癌、甲基化、微型核糖核酸-196b、微型核糖核酸、次世代定序
next generation sequencing, oral cancer, methylation, microRNA, miR-196b
統計
Statistics
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The thesis/dissertation has been browsed 5656 times, has been downloaded 28 times.
中文摘要
微型核糖核酸 (miRNA) 是一種由21到24個核苷酸所組成的內生性小片段單股核糖核酸,此種微型核糖核酸並不會轉譯任何蛋白質碼。功能失調的微型核糖核酸對於口腔鱗狀上皮細胞癌的進展扮演重要的角色,藉由沉默蛋白質編碼基因的方式,影響細胞的增生、細胞凋亡、移動、侵犯以及細胞週期。然而,在口腔鱗狀上皮細胞癌中,微型核糖核酸的具體機制以及生物性功能仍尚待釐清。
在本研究中,我們使用次世代定序法分析兩個口腔鱗狀上皮細胞癌病人的口腔鱗狀癌組織和相應癌旁正常組織的微型核糖核酸表達譜。根據次世代定序結果,我們發現 45 個微型核糖核酸顯著性的上升 (變化倍數大於2) 和 17 個微型核糖核酸下降 (變化倍數小於0.5)。在這當中,我們選擇進一步分析微型核糖核酸-196b,利用莖-環即時聚合酶鏈鎖反應分析微型核糖核酸-196b在69個成對口腔鱗狀上皮細胞癌組織的表現量。我們的結果顯示微型核糖核酸-196b在口腔鱗狀上皮細胞癌組織相較於癌旁正常組織呈現異常過度表現 (64 out of 69; 92.7%, p < 0.001)。進一步分析甲基化狀態結果顯示,在口腔癌鱗狀上皮細胞癌中微型核糖核酸-196b 的上游 CpG 島相較於癌旁正常組織呈現較低度甲基化的情況 (32 out of 69; 46.3 %),並且甲基化狀態與微型核糖核酸-196b的表現量呈負相關。在臨床意義上,我們發現微型核糖核酸-196B 啟動子的低度甲基化狀態的病人相較於高度甲基化病人具有較差的存活率。生物功能性分析發現微型核糖核酸-196b在口腔鱗狀上皮細胞癌細胞株可以促進細胞移動和侵犯;相反的抑制微型核糖核酸-196b則抑制移動和侵犯。因此,我們的研究結果顯示微型核糖核酸-196b透過調控細胞移動和侵襲,在口腔癌中扮演致癌基因的角色。因此,微型核糖核酸-196b可作為口腔鱗狀上皮細胞癌潛在的預後標誌物或標靶治癒。
Abstract
MicroRNAs (miRNAs) are a class of small endogenous single-stranded non-protein coding RNAs, about 21-24 nucleotides in length. Dysfunctional miRNAs play important role during oral squamous cell carcinoma (OSCC) progression, and contribute to modulate cell proliferation, apoptosis, migration, invasion and cell cycle by silencing protein-coding genes. However, the detailed mechanisms and biological functions of miRNAs in OSCC have yet to be fully elucidated. In this study, we performed the expression profile of human small RNAs in OSCC tissues and the corresponding adjacent normal tissues of two OSCC patients by Next generation sequencing approach. According to the profiles, we identified 45 miRNAs were significantly upregulated (fold change > 2) and 17 miRNAs downregulated (fold change < 0.5) in OSCC, respectively. Among them, the expression levels of miR-196b were further evaluated in 69 paired OSCC tissue samples using the stem-loop real-time polymerase chain reaction. Our results showed that miR-196b significantly overexpressed in OSCC tissues, as compared to the corresponding adjacent normal tissue samples (64 out of 69; 92.7%, p < 0.001). Analysis of the methylation status indicated the frequent hypomethylation of the CpG islands upstream of miR-196b in OSCC tissues compared with adjacent normal tissues (32 out of 69; 46.3 %), and the methylation status correlated inversely with miR-196b expression levels. Furthermore, the methylation status of miR-196b promoter was correlated with the poor disease-specific survival of OSCC patients (p = 0.035). Functional analysis showed that miR-196b could facilitate migration and invasion in OSCC cell lines, suppression of miR-196b by transfection with anti-miR-196b abrogated in vitro migration and invasion in OSCC cell lines. Together, our findings indicate that miR-196b plays a crucial oncogenic role in promoting cell migration and invasion during OSCC progression and thus may serve as a potential prognosis marker or therapeutic target for OSCC.
目次 Table of Contents
Introduction
1. Oral cancer……………………………………………………………………….…1
2. miRNA biogenesis………………………………………………………………..1-2
3. miRNA in oral cancer………………………………………………………………3
4. miRNA expression and risk of OSCC…………………………………………...3-4
5. DNA methylation………………………………………………………………...4-5
6. DNA methylation in oral cancer………………………………………………....5-6
7. DNA methylation and miRNA expression………………………………………...6
8. miRNA-196 and cancer…………………………………………………………..6-8
9. Next-generation sequencing and cancer……………………………….…………8-9
Specific Aims………………………………………………………………………….10
Materials and Methods
1. Patients and Tissue samples……………………………………………………….11
2. Cell lines and 5-Aza-dC Treatment……………………………………...…….11-12
3. Collection of target cells by Laser capture microdissection from frozen sections..12
4. Extraction of RNA from LCM captured cells for Next Generation Sequencing……………………………………………………………………..12-13
5. Next Generation Sequencing……………………………………………………...13
6. Hematoxylin and Eosin stain……………………………………………………...13
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7. DNA and RNA extraction…………………………………………………………14
8. Stem-loop Revers Transcription-polymerase chain reaction of Mature miRNAs..............................................................................................................14-15
9. Construction of a plasmid for the overexpression of miRNA-196b………………15
10. Establishment of stable clones………………………………………...……….15-16
11. Antagomirs assay………………………………………………………………….16
12. DNA Bisulfite conversion……………………………………..………………16-17
13. Combined Bisulfite Restriction Analysis (COBRA) and bisulfite sequencing analysis………………………………………………………………………….…17
14. Cell proliferation, cell migration assay and invasion assay…………………....17-18
15. Protein preparation and western blot…………………………………...……...18-19
16. Statistical analysis…………………………………………………………………19
Results
1. MiRNA profiling of oral squamous cell carcinoma………………………...…20-21
2. Expression level of the miR-196b in human oral squamous cell carcinoma……...21
3. Epigenetic regulation of the miR-196b in OSCC……………………………...22-23
4. Association between the DNA methylation level of miR-196b in tumor and clinicopathological features and survival…………………………………..…..….23
5. miR-196b promotes the migration and invasion of oral cancer cells but not
viii
proliferation………………………………………………..……………….23-25
6. To discover target genes of miR-196b in oral cancer cells by microarray and target prediction approach………………………………………………..……25
Discussion………………………………………………………………………….26-30
References………………………………………………………………………….31-39
Table………………………………………………………………….……………40-55
Figures…………………………………..…………………………………………56-74
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