Introduction: Gastric and colon cancer are major causes of mortality and morbidity worldwide. Gastric cancer is often detected at an advanced stage and current chemotherapeutics are only modestly effective against this neoplasm. Novel chemotherapeutics, chemopreventive agents and treatment strategies are required to prevent and treat gastric cancer. The ideal method to eliminate cancer cells may be the induction of apoptosis, further preventing cell proliferation and tumour growth. Recently, short-chain fatty acids (SCFAs) butyrate and propionate have been investigated as potential chemotherapeutic agents, particularly in colon cancer. Butyrate is reported to induce apoptosis in colon cancer cells and is demonstrated to modulate intracellular redox state by altering the levels of an antioxidant, glutathione (GSH). GSH availability is controlled by the oxidative pentose pathway (OPP). Very few studies have investigated the effects of butyrate on cell types other than colon cancer cells, and even less is known regarding the effects of propionate. This thesis investigated the potential for SCFAs to induce apoptosis in a gastric cancer cell line, Kato III, compared to the colon cancer cell line, Caco-2. Cell cycle regulation, OPP activity, GSH availability and glucose metabolism were also assessed. Methods: Initial studies developed a new technique to measure 1-13C-D-glucose metabolism. Following this, Kato III and Caco-2 colon carcinoma cells were treated with butyrate or propionate (1mM, 5mM or 10mM) or a 5mM combination of both SCFAs. The induction of apoptosis and cell cycle alterations by these SCFAs were assessed using flow cytometry. OPP activity and GSH availability were assessed in both cell lines using colorimetric techniques. Butyrate metabolism was assessed using 13C-butyrate. Results: Butyrate and propionate significantly induced apoptosis and G2-M arrest in Kato III and Caco-2 cells, although to a significantly greater extent in the latter cell line. Moreover, butyrate induced apoptosis to a significantly greater extent than propionate, in both cell lines. SCFA treatment led to the significant up-regulation of OPP activity in both cancer cell lines while GSH availability was significantly reduced. Glucose metabolism was initially increased by all SCFA treatments, however, 72hr butyrate treatment led to its reduction. Importantly, glucose metabolism was measured using a new technique developed within this thesis. The rate of butyrate metabolism was demonstrated to correlate with the sensitivity of each cell line to this SCFA. Conclusions: This thesis provides evidence that SCFAs, particularly butyrate, induce apoptosis in gastric and colon cancer cells in vitro. The response of cancer cells to SCFAs appears complex, and involves multiple distinct mechanisms and pathways, including p53, Fas, changes to intracellular redox state and glucose metabolism. The capability of butyrate to induce apoptosis also appears to be directly related to the rate of its metabolism. Butyrate has the potential to be utilised as an adjunctive therapy for the treatment of gastric cancer and colon cancer. / Thesis (Ph.D.) -- School of Molecular and Biomedical Science, 2007

<p> Using maps, correlation and multiple regression, an ecologic analysis was performed to examine the geographic distribution of cancer incidence in ontario with respect to selected ethnic, socio-economic and environmental characteristics for the 10 year period, 1976-1985. Two of the most common causes of cancer deaths, stomach and lung, were studied for each sex separately. The unit of analysis consisted of census divisions. The information used for the cancer were standardized incidence rates from the Ontario cancer Registry. The data for the ecologic variables was obtained from the 1981 Census of Canada. Two of the ecologic variables, education and income (low and median) were used to account for the effects of smoking. </p> <p> Correlation co-efficients were significant for both sites of cancer for males and females for % urban and population density revealing the possibility of a positive relationship with cancer incidence and environmental characteristics. Ethnicity was strongly related to male and female stomach cancer. </p> <p> Significant regression models were obtained for each of the cancer sites using a stepwise procedure with backward elimination. For each of the "best fit" equations, median income and education were included to control for smoking effects. Population density was significant in all equations at the 0.05 level. The percentage urban was significant for all except female stomach cancer. Manufacturing had a negative significant relationship for all cancer sites (male and female). </p> <p> Also included in the study were descriptive statistics and cancer maps to determine the strongest cancer distributions in Ontario. For each site, northern Ontario contained the highest rates. In southern Ontario, urban areas such as Hamilton-Wentworth, and Toronto-York had high rates for all cancers (except Hamilton-Wentworth for male lung cancer). </p> / Thesis / Bachelor of Arts (BA)

Plasmonic photothermal therapy (PPTT) has a rising promise for treating different cancer cells such as lymphoma or stomach cancer. Technique development of PPTT using metallic nanoparticles is developed upon a modification of the irradiation therapy using two major changes: using a less harmful visible amber light (excluding blue light) and using gold-loaded biocompatible nanoparticles. Acrylate nanoparticles were loaded with desired types of gold nanoparticles at different sizes. The gold-loaded gold nanoparticles were conjugated to cancer cells. By selectively delivering the gold nanoparticles into cancer cells, irradiating a harmless amber visible light will achieve thermal ablation of the cancer cells. Based on imaging spectroscopy, flow cytometry, and cell viability assays, results showed reduction of gold-loaded viable cancer cells upon irradiating with amber visible light, no change in the number of cancer cells with irradiating with light only. On the other hand, DNA intercalation of a trinuclear gold(I), [Au(3-CH3,5-COOH)Pz]3 (Au3) is contrasted with the standard organic intercalators ethidium and ellipticine, as investigated computationally. Frontier molecular orbital energies of intercalators and DNA base pairs were determined and found that all intercalators are good electron acceptors with Au3 being the best electron acceptor having the lowest LUMO. DNA base pairs are better electron donors having the lowest HOMO values, and from the intercalators and base pairs' HOMO/LUMO energies, it is evident the intercalators will overlap with the HOMO of DNA stabilizing the intercalators. Interaction energies (kcal/mol) were obtained as a function of distance, r (angstroms). Results show that the theoretical treatment SDD-WB97XD outperforms SDD-LSDA in both adenine-thymine (AT) systems with ethidium and Au3 intercalators. In both guanine-cytosine (GC) and AT pairs, the Au3 has the lowest interaction energies among these common intercalators, suggesting a potential intercalating drug. Experimental DNA intercalation studies were attempted and methods of finding intercalation binding constants were established, showing gold complexes have better binding constants to DNA than common intercalators to support the computational results.

published_or_final_version / abstract / Medicine / Doctoral / Doctor of Philosophy

As atividades enzimáticas e isoenzimáticas da CK e da LD foram determinadas nos tecidos gástricos neoplásico e da margem de ressecção e no soro de indivíduos com adenocarcinoma de estômago, submetidos à gastrectomia. O tecido gástrico neoplásico aapresentou índices CKBB/Cktotal e LD5/LD1, bem como atividade da LD5, superiores aos da margem de ressecção correspondente. No pré-operatório, os indivíduos estudados apresentaram elevação da atividade sérica da CK BB (100%) e da CK MB (69%). Este fato, possivelmente, resultou da liberação dessas isoenzimas pelo próprio neoplasma ou, também pelo tecido normal adjacente. As atividades séricas das isoenzimas da LD apresentaram-se dentro dos valores de referência, nesse período. Após a gastrectomia, houve aumento significativo das atividades isoenzimáticas séricas da CK e da LD relação àquelas do pré-operatório, notadamente, no 1º período pós-operatório. Tais alterações foram atribuídas à liberação dessas isoenzimas pelos tecidos lesados durante o ato cirúrgico. / Abstract not available

Lam, Man Ting. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 128-138). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Wang, Shiyan. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 123-139). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Gastric cancer is the second leading cause of cancer death worldwide and in China. The mechanism of gastric carcinogenesis is not fully understood. Epigenetic studies indicated that inactivation of tumor suppressor genes by DNA hypermethylation plays a crucial role in the progression of gastric cancer. Epigenetic inactivation of secreted frizzled-related protein (SFRP 1) by methylation plays a pivotal role on the development of various cancers. However, the role of SFRP family genes in gastric cancer remains largely unknown. We aimed to characterize the epigenetic abnormalities and discover novel biomarkers for early detection of gastric cancer. We investigated the epigenetic alterations in gastric adenocarcinoma by microarray based analysis and gene promoter hypermethylation. Based of the microarray data, we determined the functional significance and frequency of SFRP family genes hypermethylation in human gastric cancer. We screened the mRNA expression and methylation status of the SFRP family members in human gastric cancer cell lines and primary gastric cancer samples. Demethylation study of SFRP family genes were done by treating gastric cancer cell lines with 5'Aza. The biological effects of SFRP were analyzed by flow cytometry, cell viability assay and tumor growth in nude mice. SFRP1, 2, 4 and 5 were undetectable in 100% (7/7), 100% (7/7), 42.8% (3/7) and 85.7% (6/7) of gastric cancer cell lines, respectively. However, only SFRP2 showed significant down-regulation in gastric cancer compared with adjacent non-cancer samples (P&lt;0.01). Treatment with demethylation agent, 5'-Aza, restored the expression of SFRP2 in all 7 cancer cell lines. Promoter hypermethylation of SFRP2 was detected in 73.3% of primary gastric cancer samples and 20% of adjacent non-cancer tissue (P&lt;0.01). Bisulfite sequencing confirmed the density of promoter methylation in cell line, primary gastric cancer tissue and their adjacent non-cancer tissue. Transfection of SFRP2 induced cell apoptosis, inhibited proliferation in vitro and suppressed tumor growth in vivo. Furthermore, SFRP2 methylation was detected in 37.5% of samples showing intestinal metaplasia. Methylated SFRP2 was also detected in 66.7% of serum samples from cancer patients but not in normal controls. Epigenetic inactivation of SFRP2, but not SFRP1, SFRP4 and SFRP5 is a common and early event of carcinogenesis. Hence, detection of SFRP2 methylation in serum may have diagnostic value in gastric cancer patients. / by Cheng, Yuen Yee. / Adviser: FKL Chan. / Source: Dissertation Abstracts International, Volume: 69-02, Section: B, page: 0803. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 165-179). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / School code: 1307.

Array comparative genomic hybridization (array-CGH) was used in this study to analyze the chromosomal aberrations in 9 gastric cancer cell lines. Our results showed good concordance with those of conventional CGH. We correlated the results from array-CGH with expression profiling and found some novel and independent target genes which deserved further confirmation. / Gastric cancer is one of the most common malignancies worldwide and is the second most frequent cause of cancer related death. A variety of genetic and epigenetic aberrations underlie development abnormality of gastric cancer. / Taken together, our findings supported YAP1 is a functional oncogene in gastric cancer. We provided the first evidence that YAP1 exerted the oncogenic function by enhancing the capacity to activate the early response gene pathway. YAP1 could be a prognostic biomarker and potential therapeutic target for gastric cancer. / The study was focused on the putative oncogene Yes-associated Protein 1 (YAP1) located in 11q22.1. Up-regulation of YAP1 was observed in 92.3% of gastric cancer by immunohistochemistry (IHe) on gastric cancer tissue microarrays. YAP1 nuclear accumulation correlated with cancer specific survival. In addition, multivariate Cox regression showed that YAP1 was an independent predictor of short disease specific survival time for patients with early stage gastric cancer (P=0.042) in addition to T stage ( P=O.038). Knockdown YAP1 in gastric cancer cell lines MKN1 and AGS resulted in a significant reduction in proliferation, anchorage-dependent colony formation, cell invasion and cell motility. Ectopic YAP1 expression in MKN45 cells promoted anchorage-independent colony formation, induced a more invasive phenotype and accelerated cell growth both in vitro and in vivo. Microarray analysis highlighted the alteration of MAPK pathway by YAP1. We confirmed a constitutive activation of RAF/MEKJERK in YAP1-expressing MKN45 cells and further demonstrated that YAP1 enhanced serum/EGF induced c-Fos expression in gastric cancer cells. Furthermore, we demonstrated that ectopic MST1 promoted phosphorylation and cytoplasmic translocation of YAP1 and subsequently quenched the oncogenic function of YAP1 in the nucleus. / Kang, Wei. / "December 2010." / Adviser: To Kai-fai. / Source: Dissertation Abstracts International, Volume: 73-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 175-185). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

研究背景及目的：EB病毒(EBV)相關性胃癌的發病率約占胃癌的10%。近年來，越來越多的研究表明， EBV相關性胃癌的腫瘤抑制基因發生異常甲基化。然而，EBV的感染對全基因組DNA甲基化的影響尚不清楚。本研究通過分析EBV感染的細胞中全基因組DNA甲基化的情況，篩選出因EBV感染而發生甲基化的基因，並闡明靶基因在胃癌發生過程的作用。 / 方法：本研究應用穩定轉染EBV的胃癌細胞AGS (AGS-EBV)和無EBV轉染的AGS細胞為模型。採用高解析度的甲基化DNA免疫共沉澱晶片技術(MeDIP-chip)比較AGS-EBV 和AGS全基因組DNA甲基化的變化，並根據基因本體論(GO)，對EBV誘導的甲基化基因進行分類。採用RT-PCR，去甲基化處理及亞硫酸氫鈉測序(BGS)等方法驗證EBV誘導的甲基化基因。同時，採用基因敲除和過表達方法體外研究靶基因的生物學功能：通過細胞活力實驗和集落形成實驗判斷靶基因對細胞增殖的影響；通过流式细胞技术、伤口愈合实验及侵袭实验研究筛选到的靶基因生长抑素受体1（SSTR1）的功能；此外，还通過腫瘤通路基因PCR晶片分析靶基因調控的下游腫瘤相關基因。 / 结果：EBV編碼的小RNA(EBER)原位雜交方法和EBV潛伏期膜蛋白(LMP2A)的表達均證實AGS-EBV細胞中確實存在EBV的感染。和AGS細胞相比，發現AGS-EBV細胞中DNA甲基轉移酶3b(DNMT3b)的表達和活性顯著增加。AGS細胞中， LMP2A過表達後，DNMT3b的表達和活性也顯著增加。通過MeDIP-chip篩選出AGS-EBV中1,065甲基化有差異的基因，其中886基因為高甲基化。GO分析結果表明這些高甲基化基因參與KEGG信號通路。其中，六個新的高甲基化基因(MDGA2, IL15RA, SCARF2, EPHB6, SSTR1 和 REC8)在AGS-EBV細胞中的表達低於AGS；經過去甲基化處理之後，這些基因的表達水準有顯著增加。 / 通過深入研究生長抑素受體1(SSTR1)的生物學功能，發現：敲除SSTR1 能促進胃癌細胞的增殖和集落形成；通過调节G1/S期的調節因子，加快細胞進入S期，顯著增加S期的細胞數目。此外，胰腺癌細胞PANC1細胞中，SSTR1的過表達，也進一步證實SSTR1確實是一種腫瘤抑制基因。腫瘤通路基因PCR晶片結果顯示SSTR1通過促進細胞週期抑制因數(包括p15，p16，p21和p27)的表達，同時抑制CDC25A 和Myc的表達，發揮抑制增殖作用，導致細胞週期停滯在G1期，減少細胞增殖。SSTR1也通過減少凋亡相關基因的表達參與細胞凋亡的過程。此外，SSTR1還能顯著下調遷移相關基因的表達。這些結果表明，在EB病毒相關胃癌的發生過程中，SSTR1通過調節細胞週期、凋亡及遷移的有關基因，進而抑制細胞增殖，減少細胞的遷移和轉移。 / 结论：AGS感染EBV後，通過LMP2A促進DNMT3b的表達，激活DNMT3b的活性，導致886個腫瘤相關基因发生甲基化。SSTR1是一種EBV誘導的新的甲基化基因，在胃癌中具有抑制腫瘤的特性。研究表明， 由EBV誘導的SSTR1所具有的表觀遺傳學抑制作用參與EB病毒相關性胃癌的發病機制。 / Background and Aims: Epstein-Barr virus (EBV)-associated gastric cancer (GC) accounts for about 10% of all GCs. Accumulating evidences revealed aberrant rmethylation of tumor suppressor genes in EBV-associated GCs. However, the effect of EBV infection on the genome-wide aberrant DNA methylation remains unclear. We aim to profile the genome-wide EBV-associated hypermethylation in EBV-infected cells, to identify EBV-associated methylated genes and to elucidate their function in gastric carcinogenesis. / Methods: The cell model of gastric cancer AGS cells with or without stable EBV infection was used in this study. Genome-wide DNA methylation profiles were compared between AGS-EBV and AGS cells by high resolution Methyl-DNA immunoprecipitation microarry (MeDIP-chip) assay. EBV-associated methylated genes were classified according to gene ontology (GO). The novel EBV-associated methylated candidates were validated using bisulfite genomic sequencing (BGS), RT-PCR, and demethylation treatment. Biological function of one of the candidate genes (Somatostatin Receptor 1, SSTR1) was studied in vitro using gene knockdown and over-expression approaches simultaneously. Effects of SSTR1 expression on gastric cancer cell was measured by cell viability assay, colony formation assay, flow cytometry, wound-healing assay and invasion assay. Gene modulation by SSTR1 in human cancer pathways was assessed by cancer pathway PCR array. / Results: EBV infection was confirmed by EBER in situ hybridization. LMP2A expression was detected in AGS-EBV cells but not in EBV negative AGS cells. Expression and activity of DNMT3b was found to be significantly increased in AGS-EBV cells compared to AGS cells. Ectopic expression of LMP2A in AGS enhanced the expression and activity of DNMT3b. MeDIP-chip profiling identified a total of 1,065 genes differentially methylated by EBV infection (fold changes ≥2, P < 0.05) (fold-changes 2.4365.2). Gene ontology analysis indicated the enrichment of hypermethylated genes involving in important KEGG pathways. Notably, in addition to higher methylation levels confirmed by BGS, six novel hypermethylated genes (MDGA2, IL15RA, SCARF2, EPHB6, SSTR1 and REC8) were down-regulated in AGS-EBV cells as compared with AGS cells. Furthermore, demethylation treatment increased transcription levels of the six genes in AGS-EBV cells. / The biological function of SSTR1 gene was further investigated. Knockdown of SSTR1 in GC cells increased cell proliferation (P < 0.05) and colony formation ability (P < 0.01), and markedly increased cells in S phase through regulating G1/S phase mediators. Overexpression of SSTR1 in PANC1 cell line further confirmed that SSTR1 indeed was a tumor suppressor gene. Analysis of SSTR1 regulation of cancer pathway demonstrated that SSTR1 exerted antiproliferative effect by inducing cyclin-dependent inhibitors (p15, p16, p21 and p27) and inhibiting cell divison cycle 25 homolog A (CDC25A) and Myc, resulting in cell cycle arrest in G1 phase and reduction of cell proliferation. SSTR1 also took part in proliferation by decreasing expression of apoptosis regulators. Moreover, SSTR1 significantly downregulated the expression of migration-related genes, including ITGA1, ITGA2, ITGA3, ITGB5, IL8, MMP1 and PLAUR. These findings suggest that SSTR1 inhibits proliferation and reduces cell migration/invasion in gastric cancer by deregulating genes invloved in the regulation of cell cycle, survival/apoptosis and migration. / Conclusions: EBV infection in AGS cells induces genome-wide aberrant hypermethylation of 886 genes which involved in important cancer-related pathways. EBV-associated methylation is mediated by activation of DNMT3b through LMP2A. We identified and functionally characterized a novel EBV-associated methylated gene SSTR1 which exerted anti-tumor properties in GC. Epigenetic silencing of SSTR1 associated with EBV infection contributes to the pathogenesis of EBV-associated GC. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Zhao, Junhong. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 129-141). / Abstract also in Chinese. / ABSTRACT --- p.i / 摘 要 --- p.iv / Acknowledgements --- p.vi / Publications --- p.vii / Research articles --- p.vii / Conference abstracts --- p.viii / Table of contents --- p.x / list of tables --- p.xiii / list of figures --- p.xiv / list of abbreviations --- p.xvi / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- General introduction --- p.1 / Chapter 1.2 --- Gastric Cancer --- p.3 / Chapter 1.2.1 --- Eipdemiology of Gastric Cancer --- p.4 / Chapter 1.2.2 --- Pathology of Gastric Cancer --- p.8 / Chapter 1.2.3 --- Risk Factors for Gastric Cancers --- p.11 / Chapter 1.3 --- Epstein-Barr Virus-associated Gastric Cancer (EBVaGC) --- p.15 / Chapter 1.3.1 --- Historical Discovery and Harm of EBV --- p.15 / Chapter 1.3.2 --- Molecular Biology of EBV --- p.16 / Chapter 1.3.3 --- Latent and Lytic Infection of EBV --- p.18 / Chapter 1.3.4 --- EBV Products --- p.18 / Chapter 1.3.5 --- EBV-associated gastric cancer (EBVaGC) --- p.28 / Chapter 1.4 --- EBV-induced Epigenetic Alteration in Gastric Carcinogenesis --- p.36 / Chapter 1.4.1 --- Cytosine Methylation and CpG Island --- p.36 / Chapter 1.4.2 --- DNA Methylation in Gastric Cancer --- p.39 / Chapter 1.5 --- How to identify EBV-induced promoter methylation in gastric cancer --- p.45 / Chapter 1.5.1 --- Methylated DNA Immunoprecipitation (MeDIP) --- p.48 / Chapter 1.5.2 --- Combined Bisulfite Restriction Analysis (COBRA) --- p.49 / Chapter 1.5.3 --- Bisulfite Genomic Sequencing --- p.49 / Chapter 1.5.4 --- Pyrosequencing --- p.49 / Chapter Chapter 2 --- Materials and Methods --- p.51 / Chapter 2.1 --- Materials --- p.51 / Chapter 2.1.1 --- Cancer Cell Lines and Culture Condition --- p.51 / Chapter 2.1.2 --- Primary GC Samples --- p.52 / Chapter 2.2 --- EBV Encoded Nuclear RNA (EBER) in situ Hybridization (EBER-ISH) --- p.52 / Chapter 2.3 --- Western Blot Analysis --- p.53 / Chapter 2.4 --- Plasmid and Transfection --- p.56 / Chapter 2.4.1 --- Plasmid Construction and Extraction --- p.56 / Chapter 2.4.2 --- Plasmid Transfection --- p.59 / Chapter 2.5 --- Gene Expression Analysis --- p.59 / Chapter 2.5.1 --- Purification of Total RNA (RNeasy Kit, Qiagen) --- p.59 / Chapter 2.5.2 --- cDNA Reverse Transcription --- p.60 / Chapter 2.5.3 --- Semi-Quantitative PCR --- p.62 / Chapter 2.5.4 --- Quantitative Real-Time PCR (qRT-PCR) --- p.64 / Chapter 2.6 --- DNMT1 and 3b Activity Assay --- p.64 / Chapter 2.7 --- DNA Methylation Analysis --- p.64 / Chapter 2.7.1 --- Genomic DNA Extraction --- p.64 / Chapter 2.7.2 --- Genome-wide Profiling of EBV-associated DNA Methylation by MeDIP-chip --- p.65 / Chapter 2.7.3 --- Bioinformatics Analysis --- p.66 / Chapter 2.7.4 --- CpG Island Prediction and Analysis of the Targets’ Promoter Region --- p.66 / Chapter 2.7.5 --- DNA Sodium Bisulfite Modification --- p.67 / Chapter 2.7.6 --- Target Gene Methylation in GC Cell Lines --- p.67 / Chapter 2.7.7 --- Bisulfite Pyrosequencing Analysis in GC Tissue Samples --- p.70 / Chapter 2.8 --- Biological Function Analysis of SSTR1 --- p.72 / Chapter 2.8.1 --- Cell Proliferation Assay for Stable Transfection --- p.72 / Chapter 2.8.2 --- Colony Formation Assay --- p.72 / Chapter 2.8.3 --- Cell Cycle Analysis Assay --- p.72 / Chapter 2.8.4 --- Cell Migration Analysis --- p.73 / Chapter 2.8.5 --- Invasion Analysis --- p.73 / Chapter 2.8.6 --- Human Cancer Pathway Finder RT2 Profiler PCR Array Analysis --- p.74 / Chapter 2.9 --- Statistical Analysis --- p.76 / Chapter Charpter 3 --- results --- p.77 / Chapter 3.1 --- EBV Infection in AGS-EBV Cell Model --- p.77 / Chapter 3.2 --- Activation of DNMT3b in AGS-EBV Cells --- p.80 / Chapter 3.3 --- LMP2A Induced DNMT3b Activity in AGS Cells --- p.82 / Chapter 3.4 --- Genome-wide Profiling of DNA Methylation Associated with EBV Infection Using MeDIP-chip --- p.84 / Chapter 3.5 --- EBV-associated Cancer Pathways Defined by EBV-associated Promoter Methylated Genes --- p.86 / Chapter 3.6 --- CpG Hypermethylation and Transcriptional Silencing of EBV-associated Methylated Genes in AGS-EBV Cells --- p.88 / Chapter 3.7 --- Bioinformatics Analysis of SSTR1 Using University of California Santa Cruz Genome Bioinformatics (UCSC) Database and CpG Island Searcher --- p.93 / Chapter 3.8 --- COBRA Analysis of SSTR1 Promoter Methylation in GC Cell Lines --- p.93 / Chapter 3.9 --- Frequent SSTR1 Hypermethylation was Associated with EBV Positive Primary Gastric Cancer --- p.96 / Chapter 3.10 --- SSTR1 was Down-regulated in GC Cell Lines through RNA Interference --- p.103 / Chapter 3.11 --- SSTR1 Knockdown Induced Cell Proliferation in GC Cell Lines --- p.105 / Chapter 3.12 --- SSTR1 Knock-down Promoted Cells to Enter into S Phase --- p.108 / Chapter 3.13 --- SSTR1 Knock-down Increased the Migration Ability of GC --- p.110 / Chapter 3.14 --- SSTR1 Knock-down Promoted Cell Invasion --- p.112 / Chapter 3.15 --- Ectopic Expression of SSTR1 Inhibited Proliferation and Clonogenicity in PANC1 Cancer Cells --- p.114 / Chapter 3.16 --- Identification of Genes Modulated by SSTR1 --- p.116 / Chapter Chapter 4 --- Discussion --- p.119 / Chapter Chapter 5 --- Limitation of the study --- p.127 / ConclusionS --- p.128 / Reference --- p.129