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Molecular analysis of inflammation, oxidative stress, and gastric carcinogenesis: Signal transduction and gene expression changes. / Dalia Saidely

Swansea University Author: Dalia Saidely

Abstract

Long term gastric inflammation (chronic gastritis) and its coupled tumourigenic inflammatory milieu (Reactive Oxygen/ Nitrogen Species (RO/NS), cytokines, etc.) is seen to impact cells at several levels, and as such is seen to be a major driving force of gastric carcinogenesis. The goal of this inve...

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Published: 2008
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
URI: https://cronfa.swan.ac.uk/Record/cronfa42638
Abstract: Long term gastric inflammation (chronic gastritis) and its coupled tumourigenic inflammatory milieu (Reactive Oxygen/ Nitrogen Species (RO/NS), cytokines, etc.) is seen to impact cells at several levels, and as such is seen to be a major driving force of gastric carcinogenesis. The goal of this investigation was to examine the impact of inflammation, with a special focus on the oxidative stress component, on signal transduction and gene expression changes in gastric epithelial cells at the levels of Mitogen Activated Protein Kinase (MAPK) and Nuclear Factor Kappa-B (NFkappaB) pathways and downstream gene expression targets. Both in vitro and in vivo studies were performed, and a combination of microarray, real-time PCR, and western blot methodologies were employed to evaluate signalling and gene expression changes. Two in vitro models were utilised, comprising an initial chemically induced oxidative stress model, in which cells were exposed to hydrogen peroxide (H2O2), and a more elaborate inflammatory model whereby cells were exposed to leukocytes optimised to undergo an oxidative burst response. In both cases, MAPK and NFkB signal transduction pathways were seen to be affected, at the levels of the pathways themselves, and downstream gene expression targets, with over-expression of c-fos and interleukin-8 (IL-8) being the most consistently observed changes. Analysis of pre-malignant gastric biopsy specimens brought to light the potential importance of aberrant MAPK signalling and c-fos over-expression in the earliest stages of disease pathogenesis, the changes being observed most commonly in chronic inflammation/ gastritis tissues, so translating in vitro findings to a more clinically relevant setting. Overall, the findings provide strength to the notion that oxidative stress is a key player in gastric carcinogenesis, seen here at the levels of signalling and gene expression changes. Oxidative stress and the MAPK and NFkappaB pathways emerge as potential therapeutic targets for the management of gastric cancer.
Keywords: Molecular biology.;Cellular biology.
College: Faculty of Medicine, Health and Life Sciences

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