Chemerin是一種新近發現的脂肪因數，其與肥胖，代謝綜合症和炎症密切相關。Chemerin通過G蛋白偶聯受體ChemR23 發揮生物學效應。脂肪組織為分泌型Chemerin的最主要來源。最近的研究顯示Chemerin 可能與腫瘤的發生相關。本研究的目的在於確定胃癌細胞上是否存在ChemR23,以及Chemerin/ChemR23 在腫瘤侵襲過程中的作用。 / 我們首先用western blot和免疫組織化學技術在人腫瘤組織及兩株腫瘤細胞AGS和MKN28上尋找ChemR23。我們首次證實ChemR23 在胃癌細胞上表達。 / 既往研究表明，炎症因數IL-6 可上調人類內皮細胞上表達的ChemR23。為了證明IL-6 對胃癌細胞表達ChemR23的調節作用，我們將兩株胃癌細胞培養於含有不同濃度的Chemerin 的溶液中。研究證明IL-6 對於ChemR23 的表達具有濃度和時間依賴性的上調作用。 / 接下來，我們關注於Chemrin/ChemR23 在VEGF，MMP-7和IL-6 表達中的作用。我們將胃癌細胞用含有或者不含有Chemerin的溶液培養，進而測量VEGF ，MMP-7和IL-6 的表達量。進而我們將研究Chemerin 對mammalian family of mitogen-activated protein kinases (MAPKs)即：Erk，P38，Jnk的調節作用，MAPKs對於VEGF，MMP-7和IL-6 的產生起著重要的作用。我們發現Chemerin對VEGF，MMP-7和IL-6 的上調作用具有濃度和時間依賴性。Chemrin對MAPKs的啟動亦具有時間依賴性。MAPKs抑制劑可減弱Chemein相關的VEGF, MMP-7和IL-6的生成。 / 因為VEGF，MMP-7和IL-6與腫瘤的侵襲相關，我們進一步對Chemerin 在腫瘤轉移中的作用進行探索。我們使用transwell實驗工具盒來檢測腫瘤的侵襲能力。我們將AGS或MKN28細胞懸液裡加入不同濃度的Chemerin,結果是Chemerin增強腫瘤的侵襲能力（P<0.001）。為了驗證chemeri 引發的腫瘤侵襲是否通過MAPKs信號通路，我們將AGS和MKN28細胞用MAPK抑制劑處理2小時候，再加入Chemerin 0.1ng/ml。結果是Chemerin引發的腫瘤細胞侵襲可被MAPK抑制劑所抑制。 / 隨後，我們將探索人血清Chemerin濃度是否與胃癌TNM分型及組織學分型相關。研究包括36例胃癌患者的血清。TNM分型與組織病理檢查及臨床評估為依據。對於組織分型的分析，患者分為兩組，腸型和非腸型。人血清Chemerin濃度用Elisa方法測定。用one way ANOVA 進行統計學分析， II，III+IV型胃癌患者血清 Chemrin濃度明顯高於I型患者. 用獨立樣本 T test 分析，結果是非腸型胃癌患者血清Chemerin 濃度 明顯高於腸型患者 (P<0.05) / 總之，我們首次證明了胃癌細胞表達ChemR23。Chemerin /ChemR23 對腫瘤細胞分泌VEGF，MMP-7 和IL-6具有重要上調作用，該作用通過MAPKs信號通路實現。人類血清Chemerin濃度與胃癌患者TNM分析及組織性分型相關。Chemerin 可被看作是促進腫瘤侵襲的因素之一。 / Chemerin is a newly discovered adipokine which is closely associated with obesity, metabolic syndrome, and inflammatory conditions. It acts via its distinct G protein-coupled receptor ChemR23. While Chemerin is predominantly released by adipocytes, recent studies have also shown its possible correlation with carcinogenesis. This thesis aims to determine whether ChemR23 is expressed in gastric cancer, and to clarify the roles of Chemerin/ChemR23 in the invasive capacity of gastric carcinoma. / We first started by investigating the native expression of ChemR23 in human gastric cancer tissue samples and two gastric cancer cell lines, namely AGS and MKN28, using immunohistochemistry and Western blot techniques. In this set of initial experiments, ChemR23 was found to be present in gastric cancer cells with different magnitudes of expression. / Previous studies have also shown that ChemR23 synthesis in human endothelial cells was upregulatable by proinflammatory cytokines, such as IL-6. We thus investigated the biological effect of IL-6 on ChemeR23 expression in gastric cancer. By incubating the two cell lines with different concentration of recombinant IL-6, a dose- and time- dependent upregulation of ChemR23 expression was seen in both MKN28 and AGS. / We next sought to investigate the effect of Chemerin/ChemR23 on VEGF，MMP-7 and IL-6 expression. Gastric cancer cells were cultured with or without recombinant Chemerin. Corresponding VEGF, MMP-7 and IL-6 expressions were measured at sequential time points. In addition, the effect of Chemrerin on activation of mammalian family of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), P38MAPK, and c-Jun NH(2)-terminal kinase (JNK), which play a key role in VEGF, MMP-7 and IL-6 expression, was determined. Our Results revealed that Chemerin induced VEGF, MMP-7 and IL-6 expressions in gastric cancer cells in a dose- and time- dependent manner, and such an effect was reversible by MAPK inhibitors. / As VEGF, MMP-7, IL-6 are known to be associated with invasion of cancer, we therefore proceeded to determine whether Chemerin had any effect on invasiveness of gastric cancer in vitro. Commercial transwell invasion chambers were used. We found that Chemerin up-regulated the ability of invasion of gastric cancer (P<0.001). To test whether Chemerin induced gastric cancer cells invasion was mediated through MAPKs pathway, we pretreated AGS and MKN28 with or without MAPKs inhibitors 2 hours before adding Chemerin. This experiment proved that Chemerin enhanced cancer invasions were reversible by MAPK inhibitor. / In the last part of this project, the correlation between human serum Chemerin level and TNM stage/ histology of clinically collected gastric cancer samples was analyzed. This study included 36 gastric cancer patients. The cancer staging was based on a routine histopathological assessment according to the 6th UICC TNM (tumor-nodulus-metastases) system. One way ANOVA analysis showed that the mean Chemerin levels of stage II and III+IV groups were significantly higher than that of stage I cases. When serum Chemerin level was analyzed according to Lauren’s histological subtypes of the tumours, it was found to be significantly higher in the non-intestinal group when compared to the intestinal group. (P<0.05) / In conclusion, I have demonstrated for the first time that ChemR23 is expressed by gastric cancer cells. Chemerin/ChemR23 has upregulating effect on VEGF, MMP-7and IL-6 expression through the MAPK pathways. The invasive capacity of gastric cancer was significantly potentiated by Chemerin in vitro. The serum Chemerin level also has correlation with TNM stage and histology of gastric cancer. So Chemerin may be a functional onco-protein modulating the invasiveness of human gastric cancer. / 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. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Wang, Chunhu. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 129-138). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / ABSTRACT --- p.II / ACKNOWLEDGEMENTS --- p.VII / LIST OF ABBREVIATIONS --- p.VIII / LIST OF FIGURES --- p.IX / LIST OF TABLES --- p.XI / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- General introduction of Gastric Cancer --- p.1 / Chapter 1.1.1 --- Epidemiology --- p.1 / Chapter 1.1.2 --- Risk Factors --- p.2 / Chapter 1.1.3 --- Therapy --- p.6 / Chapter 1.2 --- Gastric cancer invasion --- p.8 / Chapter 1.2.1 --- The role of mitogen activated protein kinases (MAPKs) and other signaling pathways in gastric cancer invasion --- p.9 / Chapter 1.2.2 --- VEGF, MMP-7 and IL-6 and their roles in gastric cancer invasion --- p.14 / Chapter 1.3 --- Novel mediators: Chemerin/ChemR23 --- p.16 / Chapter 1.3.1 --- What is Chemerin and ChemR23 --- p.17 / Chapter 1.3.2 --- The role of Chemerin/ChemR23 in pathological conditions --- p.20 / Chapter 2.1 --- Experiment 1 :ChemR23 expression in gastric cancer --- p.24 / Chapter 2.1.1 --- Materials and methods --- p.24 / Chapter 2.1.2 --- Results --- p.26 / Chapter 2.2 --- Experiment 2: In vitro ChemR23 expression in Gastric Cancer cell culture and its interaction with IL-6 --- p.32 / Chapter 2.2.1 --- Materials and methods --- p.32 / Chapter 2.2.2 --- Results: --- p.35 / Chapter 2.3 --- Discussion --- p.45 / Chapter Chapter 3 --- Chemerin activates FAK, MAPK and Akt signal pathway on gastric cancer --- p.50 / Chapter 3.1 --- Materials and methods --- p.50 / Chapter 3.1.1 --- Reagents and antibodies： --- p.51 / Chapter 3.1.2 --- Cell cultures and treatment --- p.51 / Chapter 3.1.3 --- MTT assay for the effect of Chemerin on gastric cancer proliferation --- p.52 / Chapter 3.1.4 --- ChemR23 siRNA transfection --- p.52 / Chapter 3.1.5 --- Western blot analysis. --- p.53 / Chapter 3.1.5 --- Statistical analysis. --- p.54 / Chapter 3.2 --- Results --- p.54 / Chapter 3.2.1 --- MTT assay result --- p.54 / Chapter 3.2.2 --- Chemerin activates FAK signal pathways --- p.56 / Chapter 3.2.3 --- Chemerin activate MAPK signal pathways --- p.58 / Chapter 3.2.4 --- Chemerin induced Akt activation --- p.63 / Chapter 3.2.5 --- Chemerin activates MAPK pathways through ChemR23 --- p.65 / Chapter 3.3 --- Discussion --- p.69 / Chapter Chapter 4 --- Chemerin up-regulates VEGF, MMP-7 and IL-6 expression throug MAPK pathway on gastric cancer --- p.73 / Chapter 4.1 --- Materials and methods --- p.73 / Chapter 4.1.1 --- Reagents and antibodies： --- p.73 / Chapter 4.1.2 --- Cell cultures and treatment --- p.74 / Chapter 4.1.3 --- ChemR23 siRNA transfection --- p.74 / Chapter 4.1.4 --- Treatment MAPK inhibitors --- p.75 / Chapter 4.1.5 --- uantitative reverse transcript (RT)-PCR assay --- p.75 / Chapter 4.1.6 --- Western blot analysis --- p.76 / Chapter 4.1.7 --- Statistical analysis. --- p.77 / Chapter 4.2 --- Results --- p.78 / Chapter 4.2.1 --- Chemerin up-regulated VEGF, MMP-7, IL-6 expression --- p.78 / Chapter 4.2.2 --- Chemerin induced VEGF and MMP-7expression through ChemR23 --- p.87 / Chapter 4.2.3 --- Chemerin induced VEGF, MMP-7 and IL-6 expression through MAPK pathways --- p.91 / Chapter 4.3 --- Discussion: --- p.96 / Chapter Chapter 5 --- Chemerin enhances gastric cancer invasiveness through the MAPK pathways --- p.100 / Chapter 5.1 --- Materials and methods --- p.100 / Chapter 5.1.1 --- Reagents and antibodies： --- p.100 / Chapter 5.1.2 --- Cell culture and treatments --- p.101 / Chapter 5.1.3 --- Tumor invasion potential evaluated with Transwell invasion chambers --- p.101 / Chapter 5.1.4 --- Statistical analysis. --- p.102 / Chapter 5.2 --- Results: --- p.103 / Chapter 5.2.1 --- Chemerin increased gastric cancer cells invasion abilities --- p.103 / Chapter 5.2.2 --- Chemerin increased gastric cancer cells invasion abilities through MAPK pathways --- p.104 / Chapter 5.3 --- Discussion: --- p.109 / Chapter Chapter 6 --- Chemerin relates with TNM stage and histology of gastric cancer --- p.113 / Chapter 6.1 --- Materials and methods --- p.113 / Chapter 6.1.1 --- Study population --- p.113 / Chapter 6.1.2 --- Serum Chemerin level measurements --- p.114 / Chapter 6.1.3 --- Statistical analysis --- p.115 / Chapter 6.2 --- Results: --- p.115 / Chapter 6.2.1 --- Serum Chemerin level in healthy subject plus gastric cancer patients followed normal distribution but did not follow homogeneity of variances --- p.115 / Chapter 6.2.2 --- Serum Chemerin level in gastric cancer patients was higher than healthy subjects --- p.116 / Chapter 6.2.3 --- Serum Chemerin level in gastric cancer followed normal distribution and homogeneity of variances --- p.120 / Chapter 6.2.4 --- Human serum Chemerin level was related to gastric cancer TNM stage --- p.121 / Chapter 6.2.5 --- Association between human serum Chemerin level and histology --- p.123 / Chapter 6.3 --- Discussion --- p.125 / Chapter Chapter 7: --- Conclusion and future plan --- p.127 / Reference --- p.129

This thesis explores the variety of ways in which scientific views of genetic testing are portrayed in the realm of popular culture. As a case study, I have used the identification of the gene for hereditary stomach cancer which occurred in New Zealand in 1998, and was the result of a partnership between the affected whanau and scientists from the University of Otago. Both the empirical and theoretical findings of this project have shown how such accounts are not neutral or transparent. Rather, they are positioned to represent certain values and ideas, and this is even more evident when those affected are Maori. However, considering textual representations of the gene and cancer has revealed the importance of taking into account the fact that these 'things' are also physical and material. I consider the implications of this and consider the ways in which the whanau health workers negotiate the fetishism apparent in biomedicine. Despite its misgivings, biomedicine has immense benefits, some of which the whanau have manipulated and appropriated for their own good, although they do so on their own terms. Despite the many complexities involved in this case study, this is a positive and hopeful story where those involved in the stomach cancer gene project have emerged with improved solutions.

published_or_final_version / abstract / toc / Pharmacology / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Medicine / Doctoral / Doctor of Philosophy

Induction of ITF expression significantly enhanced invasion of Rat-2 (1.8-folds) without promoting proliferation. The increase in invasiveness was accompanied by an upregulation of beta-catenin (18.0%) and MMP-9 (67.8%), and downregulation of E-cadherin (29.7%) and TIMP-1 (34.7%). Silencing ITF in MKN45 markedly delayed the onset of tumor progression by Day 6 and reduced the tumor volume by 85% by Day 14. ITF siRNA significantly attenuated angiogenesis in vivo and in vitro. The effects of silencing ITF were mediated through transcriptional upregulation of the Bax (114%), Bak (89%), Ang-2 (89%) and Tie-2 (399%). Bcl-2, Bcl-xL, VEGF and Ang-1 expressions were not significantly altered. Silencing ITF in gastric cancer cells increased the effect of cisplatin-induced apoptosis in a dose-dependent manner. / Our findings suggested that ITF plays a role in invasion, proliferation and angiogenesis. The mechanisms involve regulation of catenin-cadherin complexes, balance of MMPs/TIMPs, proapoptotic Bcl-2 family members and Ang-2/Tie-2 system. Silencing ITF enhanced the chemotherapeutic response of gastric cancer cells to cisplatin. Blocking ITF expression using RNA interference may have a potential therapeutic application in gastric cancer. (Abstract shortened by UMI.) / The aim of this project was to define the role of ITF in gastric carcinogenesis. The thesis consisted of two parts of scientific studies to investigate the effects of: inducing ITF expression on the proliferation and invasion of non-tumorigenic rat fbroblast cells (Part 1); and silencing ITF on the proliferation, angiogenesis and chemotherapeutic response in gastric cancer cells (Part 2). / Chan Yik Wai. / "August 2005." / Adviser: Francis Ka Leung Chan. / Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3719. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 124-139). / 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 in English and Chinese. / School code: 1307.

Wang, Ruizhi. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 109-134). / Abstracts in English and Chinese. / Acknowledgement --- p.i / Publications --- p.ii / Abstract --- p.iv / 中文摘要 --- p.viii / Abbreviations --- p.xi / List of tables --- p.xiv / List of figures --- p.xv / Contents --- p.xvii / Chapter Chapter One: --- Introduction --- p.1 / Chapter 1.1 --- Epidemiology of gastric cancer --- p.2 / Chapter 1.2 --- Risk factors of gastric cancer --- p.3 / Chapter 1.3 --- Treatment of gastric cancer --- p.4 / Chapter 1.3.1 --- Surgical treatment --- p.4 / Chapter 1.3.2 --- Chemotherapy --- p.4 / Chapter 1.3.3 --- Targeted therapy --- p.5 / Chapter 1.4 --- "Phenotypes of cell death: apoptosis, oncosis and autophagy" --- p.9 / Chapter 1.4.1 --- Cell death --- p.9 / Chapter 1.4.2 --- Apoptosis --- p.10 / Chapter 1.4.2 --- Oncosis --- p.11 / Chapter 1.4.3 --- Autophagy --- p.12 / Chapter 1.4.4 --- p53 --- p.13 / Chapter 1.5 --- Heme oxygenase-1 --- p.14 / Chapter 1.5.1 --- General introduction of Heme oxygenase --- p.14 / Chapter 1.5.2 --- Anti-oxidant function of HO-1 --- p.15 / Chapter 1.5.3 --- Anti-inflammation function of HO-1 --- p.17 / Chapter 1.5.4 --- Pro-angiogenesis role of HO-1 --- p.18 / Chapter 1.5.5 --- HO-1 and cell proliferation --- p.19 / Chapter 1.5.6 --- HO-1 as a therapeutic target for tumors --- p.20 / Chapter 1.6 --- Objectives of study --- p.22 / Chapter Chapter Two: --- Methods and materials --- p.26 / Chapter 2.1 --- Gastric cancer cell lines --- p.27 / Chapter 2.2 --- Cell proliferation detection --- p.27 / Chapter 2.2.1 --- "MTT(3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)assay" --- p.27 / Chapter 2.2.1.1 --- Introduction of MTT assay --- p.27 / Chapter 2.2.1.2 --- Processes of MTT assay --- p.27 / Chapter 2.2.1.3 --- Cell proliferation and cytotoxicity of drugs --- p.28 / Chapter 2.2.2 --- Detection of apoptosis by TUNEL assay --- p.29 / Chapter 2.2.2.1 --- TUNEL (Terminal uridine deoxynucleotidyl transferase dUTP nick end labeling) --- p.29 / Chapter 2.2.2.2 --- Sample preparation --- p.29 / Chapter 2.3 --- Detection of cell cycle by flow cytometry --- p.32 / Chapter 2.3.1 --- Cell cycle --- p.32 / Chapter 2.3.2 --- Sample preparation --- p.33 / Chapter 2.3.3 --- Flow cytometry analysis --- p.34 / Chapter 2.4 --- Detection of mitochondrial membrane potential(ΔΨm) --- p.35 / Chapter 2.4.1 --- Sample preparation --- p.35 / Chapter 2.4.2 --- Mitochondrial membrane potential(ΔΨm) analysis by flow cytometry --- p.36 / Chapter 2.5 --- Detection of proteins investigated in the project --- p.37 / Chapter 2.5.1 --- Antibodies --- p.37 / Chapter 2.5.2 --- Sample Preparation --- p.39 / Chapter 2.5.2.1 --- Cell culture --- p.39 / Chapter 2.5.2.2 --- Protein extraction --- p.39 / Chapter 2.5.2.3 --- Protein assay --- p.41 / Chapter 2.5.2.4 --- Final loading protein --- p.42 / Chapter 2.5.3 --- Western blotting --- p.43 / Chapter 2.6 --- Statistical analysis --- p.45 / Chapter Chapter three: --- Roles of HO-1 in 5-FU treatment for gastric cancer cell lines --- p.47 / Chapter 3.1 --- Cell proliferations with drug treatments --- p.48 / Chapter 3.1.1 --- MTT assay --- p.48 / Chapter 3.1.1.1 --- Introduction --- p.48 / Chapter 3.1.1.2 --- Method and results --- p.49 / Chapter 3.1.2 --- TUNEL assay --- p.58 / Chapter 3.1.2.1 --- Introduction --- p.58 / Chapter 3.1.2.2 --- Method and results --- p.59 / Chapter 3.2 --- HO-1 expression with drug treatments --- p.63 / Chapter 3.2.1 --- Introduction --- p.63 / Chapter 3.2.2 --- Method and results --- p.64 / Chapter 3.3 --- Discussion --- p.72 / Chapter Chapter Four: --- Mechanism responsible for the additive effect of 5-FU and ZnPP --- p.77 / Chapter 4.1 --- Cell cycle arrest after drug treatments --- p.78 / Chapter 4.1.1 --- Introduction --- p.78 / Chapter 4.1.2 --- Method and results --- p.79 / Chapter 4.2 --- Mitochondrial dependent and independent pathway --- p.85 / Chapter 4.2.1 --- Introduction --- p.85 / Chapter 4.2.2 --- Method and results --- p.87 / Chapter 4.3 --- Alteration of apoptotic proteins in gastric cancer cell death after drug treatments --- p.91 / Chapter 4.3.1 --- Introduction --- p.91 / Chapter 4.3.2 --- Method and results --- p.94 / Chapter 4.4 --- Discussion --- p.101 / Chapter Chapter Five: --- Summary and future prospects --- p.107 / Chapter 5.1 --- Summary --- p.108 / Chapter 5.1.1. --- The inhibition of HO-1 enhances the sensitivity of gastric cancer cells to 5-FU --- p.108 / Chapter 5.1.2 --- Apoptosis induced by 5-FU plus HO-1 inhibitor ZnPP is through a mitochondrial-related pathway in MKN28 and MKN45 --- p.109 / Chapter 5.1.3 --- 5-FU plus ZnPP induces apoptosis in a caspase-dependent pathway in MKN45 while in both caspase-dependent and caspase-independent pathway in MKN28 --- p.110 / Chapter 5.2 --- Future prospects --- p.111 / References --- p.113

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

published_or_final_version / abstract / Surgery / Master / Master of Philosophy

published_or_final_version / abstract / toc / Medicine / Doctoral / Doctor of Philosophy

published_or_final_version / Pathology / Master / Master of Philosophy