The role of peroxisome proliferator activated receptor alpha (PPARα) in the effect of piroxicam on colon cancer

McCartney, Karen M. (2015) The role of peroxisome proliferator activated receptor alpha (PPARα) in the effect of piroxicam on colon cancer. PhD thesis, University of Nottingham.

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Abstract

Studies with APCMin/+ mice and APCMin/+ PPARα-/- mice were undertaken to investigate whether polyp development in the mouse gut was mediated by PPARα. Additionally, the effect of piroxicam treatment dependency on PPARα was assessed.

Results showed the number of polyps in the colon was significantly higher in APCMin/+ PPARα-/- mice than in APCMin/+ mice, whilst in the small bowel the difference was not significant.

Analysis of gene expression in the colon with Affymetrix® microarrays demonstrated the largest source of variation was between tumour and normal tissue. Deletion of PPARα had little effect on gene expression in normal tissue but appeared to have more effect in tumour tissue.

Ingenuity pathway analysis of these data showed the top biological processes were growth & proliferation and colorectal cancer. Collectively, these data may indicate that deletion of PPARα exacerbates the existing APCMin/+ mutation to promote tumorigenesis in the colon.

95 genes from Affymetrix® microarray data were selected for further analysis on Taqman® low density arrays. There was good correlation of expression levels between the two array types. Expression data of two genes proved particularly interesting; Onecut homeobox 2 (Onecut2) and Apolipoprotein B DNA dC  dU - editing enzyme, catalytic polypeptide 3 (Apobec3). Onecut2 was highly up-regulated in tumour tissue. Apobec3 was up-regulated in APCMin/+ PPARα-/- mice only; suggesting expression was mediated via PPARα.

There was a striking increase in survival accompanied by a marked reduction in small intestinal polyp numbers in mice of either genotype that received piroxicam. Taqman® low density array analysis of the same 95 genes as previously showed similar expression levels in piroxicam-treated APCMin/+ mice and APCMin/+ PPARα-/- mice. Taken together, these data indicated that the effect of piroxicam treatment was not mediated via PPARα.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Hawkey, C.J.
Bennett, A.J.
Keywords: Peroxisome proliferator activated receptor, Colon cancer, Piroxicam
Subjects: QS-QZ Preclinical sciences (NLM Classification) > QU Biochemistry
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Medicine
Item ID: 29153
Depositing User: McCartney, Karen
Date Deposited: 13 Oct 2015 10:39
Last Modified: 14 Sep 2016 16:18
URI: http://eprints.nottingham.ac.uk/id/eprint/29153

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