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Title: The effect of butyrate on VEGF and Neuropilin-1 expression in colon cancer
Author: Yu, Chen-Wei
ISNI:       0000 0004 2720 6789
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2012
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Colorectal cancer is the third most common cancer and the second cause of cancer death in the UK. The incidence of colorectal cancer has been shown to be decreased in populations with a high dietary fibre intake. This effect is thought be attributable in part to the cellular actions of butyrate, a short-chain fatty acid (SCF A) produced by fermentation of fibre in the human colon lumen. Butyrate has been implicated in cellular homeostasis of normal colonic mucosa and it is thought to underwrite the chemoprotective effect of fibre. Angiogenesis is essential for tumour development and is stimulated at the earliest stages of the adenomacarcinoma sequence in the colon with an increase in VEGF expression. Neuropilin-l (NRP-l) is a transmembrane receptor for VEGF and semaphorins. We demonstrate here that butyrate downregulates NRP-l and VEGF at mRNA and/or protein levels in colorectal cancer cell lines. NRP-l is a known transcriptional target of Sp 1, whose activity is regulated by butyrate. We show that NRP-l down-regulation by butyrate is associated with decreased binding affinity of Sp 1 binding elements on the NRP-l promoter. Previous studies have suggested that NRP-l expression is limited within normal tissues of the gastrointestinal tract. We show that the VEGF receptor NRP-l is lower in subjects with elevated butyrate in morphologically normal tissue distant to adenomas, but the expression is lower and not butyrate responsive in the field around adenomas. We sought to investigate whether NRP-l expression is associated with enteroendocrine cells (EEC) and how each marker corresponds to butyrate level. The EEC marker chromogranin A (CgA) positive cell number is negatively correlated with butyrate in normal tissue but this relationship is lost at the field. A colocalisation analysis reveals that only 11 % of NRP-l expressing cells are also positive for CgA. Our data suggest that NRP-l is butyrate responsive in the human colon in vitro and in vivo but the majority is not expressed in the CgA + EEC population. The number of CgA + EEC is likewise influenced by butyrate; however, field effects cause this relationship to be lost. The down-regulation of the apoptosis and angiogenesis regulator NRP-l by SCF A butyrate may contribute a novel mechanism to the chemopreventive effect of dietary fibre.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available