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研究生:林怡伶
研究生(外文):Yi-Ling Lin
論文名稱:RCC1基因和微型核醣核酸在胃癌之表觀遺傳學調控
論文名稱(外文):Epigenetic Regulation of RCC1 gene and MicroRNAs in Gastric Carcinoma
指導教授:陳全木陳全木引用關係
口試委員:吳誠中葛其梅陳春榮杜旻育
口試日期:2016-07-21
學位類別:博士
校院名稱:國立中興大學
系所名稱:生命科學系所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:英文
論文頁數:119
中文關鍵詞:胃癌表觀遺傳DNA甲基化組蛋白修飾微型核醣核酸差異性甲基化雜交法腫瘤分化即時定量檢測方法微滴式數位核酸偵測
外文關鍵詞:Gastric carcinomaepigeneticDNA methylationhistone modificationsmicroRNAdifferential methylation hybridizationtumor differentiationquantitative reverse transcriptase polymerase chain reactiondroplet digital PCR
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根據統計,胃癌是目前常見的腫瘤之一,其罹患率位居第三位。近年來胃癌之罹患率有下降趨勢,但至目前為止胃癌形成的機制仍舊不甚清楚。胃癌發生原因很多,包括基因及表觀遺傳變異等。在癌症腫瘤發生的過程中,表觀遺傳(epigenetic)變異是屬於不改變核苷酸序列而改變個體的表現型(phenotype)或基因表現的基因調控方式,造成這些變異的調控方式包含 DNA甲基化(DNA methylation)、組蛋白修飾(histone modification)及微型核醣核酸(microRNA)表現等機制,因此我們欲利用具有高通量且自動化分析的生物晶片來進一步剖繪基因在胃癌表現之差異。DNA甲基化是表觀遺傳變異的調控方式之一,因此在本研究中,先以甲基化晶片技術(差異性甲基化雜交法,DMH)進行基因體全面性偵測胃腫瘤組織的甲基化程度差異,以期能找出與胃癌相關基因。根據初步晶片分析結果,篩選出Regulator of chromosome condensation 1 (RCC1),以甲基化分析及其它生物技術方法驗證所篩選出之基因,結果顯示RCC1表現與腫瘤分化(differentiation)及侵犯程度(depth of invasion)有關,推論RCC1在胃癌的形成過程中扮演抑癌基因(tumor suppressor) 的角色。另一方面,胃癌常因發現的晚及預後較差,存活率也較差,因此若能早期診斷出胃癌,可提升預後及存活率。近來研究指出血漿及血清中微型核醣核酸因容易取得且在血液中是穩定的,因此微型核醣核酸可作為人類疾病預測、分類及癌症治療的生物性指標。本研究利用微型核醣核酸晶片分析胃癌患者微型核醣核酸表現圖譜,根據分析統計找出有顯著表現差異之微型核醣核酸。利用即時定量檢測方法(qRT-PCR)及微滴式數位核酸偵測(droplet digital PCR) 針對顯著表現差異微型核醣核酸中之miR-4728-3p, miR-6716-3p, miR-3184-3p 和miR-4290做進一步驗證,分析其表達差異。結果發現,血清中的miR-4728-3p、miR-6716-3p和miR-3184-3p在胃癌組中的表達量皆是上升,且在微滴式數位核酸偵測之定量檢測有統計上的差異。結果證實miR-4728-3p、miR-6716-3p和miR-3184-3p可作為胃癌篩檢非侵入性之生物性指標。但仍需分析更多胃癌檢體再加以確認。

Gastric carcinoma (GC) remains one of the most common cancers and the third leading cause of cancer deaths worldwide. Despite a steady decline in GC incidence, GC still represents a major health problem, but the molecular mechanisms underlying the development of GC are still poorly understood. GC is a multi-factorial disease that involves both genetic and epigenetic modification. The process of carcinogenesis was always followed with the genetic variations that are not changes in nucleotide sequence but changes in the phenotype to affect gene regulation. It is called epigenetic modification. These modifications are including DNA methylation, histone modifications and microRNA expression mechanisms. Therefore, we would like to use the concept of biochip, high-throughput and automated analysis, to characterize and realize the GC genome wide profile. Here, we were using differential methylation hybridization (DMH) to profile methylation alterations of CGIs on patients with GC. According to preliminary microarry data analysis, Regulator of chromosome condensation 1 (RCC1) was selected to verify the methylation and gene expression status by methylation analysis and other biotechnological methods. Our data indicate that RCC1 expression is frequently lost in poorly differentiated gastric cell lines and gastric carcinoma tissues. Loss of RCC1 expression is correlated with tumor differentiation and depth of invasion. These findings suggest that RCC1 may play a tumor suppressor role in GC. On the other hand, most GC often diagnosed with advanced stage, but the prognosis and overall 5-year survival rate of GC patients remains approximately 20%. Thus, early detection of GC is a key measure to reduce the mortality and improve the prognosis of GC. Previous studies indicated that miRNAs circulate in highly, stable, cell-free forms in blood. Serum and plasma miRNAs are relatively easy to access, circulating miRNAs have great potential to serve as non-invasive biomarkers. To investigate the potential of serum miRNAs as noninvasive biomarkers for detection of GC, miRNA array was used to identify and validate the differential serum miRNAs in GC patients. The miR-4728-3p, miR-6716-3p, miR-3184-3p and miR-4290 were selected as a candidate for a further analysis. These miRNAs were validated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and droplet digital PCR (ddPCR). The results showed miR-4728-3p, miR-6716-3p and miR-3184-3p had significantly higher copy number in serum of GC patients compared with cancer-free controls. These results suggest that miR-4728-3p, miR-6716-3p and miR-3184-3p have potential as novel non-invasive biomarkers for detection of GC, but need to analyzed more GC samples.

Contents
中文摘要 i
Abstract ii
Chapter I
Literature reviews 1
I. Gastric carcinoma 2
(I) Histologic classification of Gastric Carcinoma 2
(II) Risk factors 5
(III) Genetic factors 7
II. Epigenetics regulation in GC 11
(I) DNA methylation 11
1. Tumor related gene methylation in gastric tumorigenesis 12
2. Method for DNA methylation analysis 19
(II) Histone modification 25
1. Histone methylation 25
2. Histone-modifying enzyme 26
3. Combinatorial modification of DNA and histones 27
(III) MicroRNA regulation 27
1. MicroRNA characters 27
2. MicroRNA alternations in GC 28
3. Methodology of microRNA detection 31
III. Research rationale and approaches 33
(I) Aim I 33
(II) Aim II 34
Chapter II
Methylation-silencing RCC1 Expression is Associated with Tumorigenesis and Depth of Invasion in Gastric Cancer 35
I. Abstract 36
II. Introduction 37
III. Materials and Methods 40
(I) Tissue and DNA samples 40
(II) Differential methylation hybridization (DMH) microarray assay 40
(III) Cell culture 43
(IV) Quantitative reverse transcription PCR (qRT-PCR) 43
(V) Western blot analysis 43
(VI) Primer design and PCR amplification for gene methylation study 44
(VII) In vitro transcription and T-cleavage (RNase A digestion) assay 44
(VIII) MALDI-TOF mass spectrometry for DNA methylation measurement 45
(IX) Immunohistochemical staining of tissue microarray 45
(X) Statistical analysis 46
IV. Results 47
(I) Identification of hypermethylation genes from GC by DMH microarray 47
(II) mRNA expression of RCC1 in different human gastric cancer cell lines 48
(III) Protein expression levels of RCC1 in different gastric cancer cell lines 48
(IV) MALDI-TOF mass spectrometry analysis of CpG site methylation in the
RCC1 gene in different human gastric cancer cell lines 56
(V) Correlation analysis of RCC1 expression and clinicopathological characteristics
of GC 58
V. Discussion 64
Chapter III
Serum MicroRNAs Expression Profiling: Identification of miR-4728-3p, miR-6716-3p and miR-3184-3p As Novel Diagnostic Markers in Gastric Carcinoma 68
I. Abstract 69
II. Introduction 70
III. Materials and Methods 73
(I) Patients and serum samples 73
(II) MicroRNA expression profiling 73
(III) Identification of differentially expressed miRNAs 74
(IV) miRNA quantification by qRT-PCR 74
(V) Droplet digital PCR workflow 75
(VI) Statistical analysis 76
IV. Results 78
(I) Serum miRNAs expression profiling of GC patients by human miRNA
microarray 78
(II) Identification of differentially expressed miRNA in GC 78
(III) Validation of differentially expressed miRNAs by qRT-PCR 82
(IV) Definition of miRNA copy numbers in serum samples by ddPCR 82
V. Discussion 95
Conclusions 98
References 100








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