AbstractColorectal cancer (CRC) is the third most common cancer worldwide. Observational studies and randomised controlled trials for vascular events have shown aspirin as a possible chemopreventative agent in CRC. Aspirin is a well-established inhibitor of the (COX)/(PGE2) signalling pathway. However, an aspirin derivative (NCX-4016) that does not inhibit COX activity was reported to have a better chemopreventative effect in a mouse model of colon cancer implicating other unknown aspirin anti-cancer effects. More recently aspirin has been reported to induce post-transcriptional modifications, specifically, protein and histone acetylation.
The aim of this PhD thesis was to investigate the effect of short-term and long-term aspirin exposure in colorectal adenoma cells (RG/C2) by looking at the regulation of cell growth as well as changes in DNA methylation, gene and protein expression. Mendelian randomisation (MR) was used to assess whether variations in aspirin metabolite levels are associated with risk of CRC.
Through combining multiple ‘omics, short-term aspirin was not found to regulate genome-wide DNA methylation but was implicated in regulating specific gene expression e.g. suppressing STMN1. This led to a reduction in cell migration, which may partly explain the anti-metastatic function of aspirin. Conversely, cells exposed long-term to aspirin (≥18 weeks) were less responsive to aspirin’s growth inhibition. Long-term treatment resulted in a genome-wide effect on DNA methylation, highlighting a previously unreported role for aspirin in epigenetic regulation. Finally, the MR approach showed a possible association between aspirin metabolism and cancer risk, complementing other epidemiological evidence with regards to aspirin use and cancer risk.
For the first time, combining population-based and laboratory-based methods have identified possible new mechanisms of aspirin’s action. Genetic variants may help inform the effect of aspirin use on CRC risk and epigenetic modifications from long-term use could help identify patients who become less responsive to the drug.
|Date of Award||23 Jan 2019|
|Supervisor||Ann C Williams (Supervisor) & Caroline L Relton (Supervisor)|