Over the last three decades, there has been a sharp rise in the incidence of oesophageal adenocracinoma (OA) in the UK. The cause of this rising trend remains unknown. Chronic symptomatic Gastro-Oesophageal Reflux Disease (GORD) has been associated with Barrett's oesophagus (BO), a premalignant stage of OA. The process how acid exposure drives the metaplasia-dysplasia-neoplasia sequence is not known. Oxidative stress plays vital role in carcinogenesis. Selenium is a trace metal element in our diet essential for anti-oxidant selenoproteins synthesis, such as glutathione peroxidases (GPxs). GPxs play a vital role in humans to fight oxidative stress. Epidemiological studies showed that high serum selenium levels are associated with a lower incidence of oesophageal and gastric cardia cancer. This thesis hypothesised that chronic GORD is an initiator of OA pathogenesis by exposing the lower oesophagus to chronic pulse acid, which results in radical oxygen species (ROS) production and oxidative stress damage. GORD patients with suboptimal selenium status are more susceptible to pulse-acid induced oxidative damage because of poor anti-oxidative defence system. The combination of pulse acid exposure and low selenium status potentially drives the OA pathogenesis. The study aims to investigate the effect of pulse-acid exposure, selenium status and its supplementation on cellular proliferation and apoptosis, key processes in carcinogenesis. The study also further investigated the potential pathways through which the pulse acid and low selenium could trigger the carcinogenesis. Ex vivo study was also conducted to examine the selenium status among BO and OA patients, including analysis of single nucleotide polymorphism (SNP) of GPx4 among these patients. The results showed that pulse-acid exposure increased cellular survival and suppressed apoptosis. This result was consistent with previous studies conducted by other researchers. Selenium supplementation at supra-optimal level (100 nM) was shown to potentially mitigate the proliferative effect induced by pulse-acid exposure. Pulse acid exposure was shown to induce ROS production in vitro. This could be mitigated by selenium supplementation. The mitigating effect was likely to be mediated by GPx1, and GPx4, selenoenzymes that are capable of reducing ROS. The study also revealed that apoptosis suppression by selenium supplementation was probably mediated by p53 tumour suppressor gene, but not via Bcl-2 protein. Ex vivo study results showed that OA patients have a 54% significant lower GPx4 mRNA expressions compared to the normal subjects, while the Barrett's subjects were in between OA and Normal. This is in line with the hypothesis that the severity of the disease is closely linked with the levels of anti-oxidant enzymes expression. Expectantly, patients with BO have higher, although not statistically significant, serum selenium compared to the control group. Single nucleotide polymorphism (SNP) of GPx4 could be an explanation for the reason OA and BO patients were unable to synthesise GPx despite an adequate serum selenium level, this rendered them more susceptible to ROS induced oxidative damage. These findings might have potential therapeutic implications for BO and OA. Targeted selenium supplementation could be a cost effective way of OA cancer prevention. Target screening to identify subjects with certain Genotype or SNP, could ensure early intervention to prevent cancer development. A long term, well designed, randomised, placebo controlled selenium supplementation trial to examine the clinical efficacy of selenium supplementation in OA prevention is warrant.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:600102 |
| Date | January 2013 |
| Creators | Goh, Aik Han |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=206626 |
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