Keratin 8 expression in colon cancer associates with low faecal butyrate levels.

Abdul Q Khan,Steven R Brown,Jonathan P Bury,Bernard M Corfe,Stuart A Riley

doi:10.1186/1471-230x-11-2

Abdul Q Khan, Steven R Brown + Show 3 more

Open Access

https://doi.org/10.1186/1471-230x-11-2

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Abstract

BackgroundButyrate has been implicated in the mechanistic basis of the prevention of colorectal cancer by dietary fibre. Numerous in vitro studies have shown that butyrate regulates cell cycle and cell death. More recently we have shown that butyrate also regulates the integrity of the intermediate filament (IF) cytoskeleton in vitro. These and other data suggest a link between the role of diet and the implication of a central role for the keratin 8 (K8) as guardian of the colorectal epithelium.MethodsIn this cross-sectional study possible links between butyrate levels, field effects and keratin expression in cancer were addressed directly by analysing how levels of expression of the IF protein K8 in tumours, in adjacent fields and at a distant landmark site may be affected by the level of butyrate in the colon microenvironment. An immunohistochemical scoring protocol for K8 was developed and applied to samples, findings were further tested by immunoblotting.ResultsLevels of K8 in colorectal tumours are lower in subjects with higher levels of faecal butyrate. Immunoblotting supported this finding.Although there were no significant relationships with butyrate on the non-tumour tissues, there was a consistent trend in all measures of extent or intensity of staining towards a reduction in expression with elevated butyrate, consistent with the inverse association in tumours.ConclusionsThe data suggest that butyrate may associate with down-regulation of the expression of K8 in the cancerized colon. If further validated these findings may suggest the chemopreventive value of butyrate is limited to early stage carcinogenesis as low K8 expression is associated with a poor prognosis.

Highlights

Butyrate has been implicated in the mechanistic basis of the prevention of colorectal cancer by dietary fibre
Score 3 if more than 60% of cells were positively stained for keratin 8 (K8); 2 if around half of the cells stained and 1 if less than 40% of the cells were stained with K8
The pattern of K8 expression in normal and cancer mucosa was reported by Fujiski [34]

Summary

Introduction

Butyrate has been implicated in the mechanistic basis of the prevention of colorectal cancer by dietary fibre. Numerous in vitro studies have shown that butyrate regulates cell cycle and cell death. More recently we have shown that butyrate regulates the integrity of the intermediate filament (IF) cytoskeleton in vitro. These and other data suggest a link between the role of diet and the implication of a central role for the keratin 8 (K8) as guardian of the colorectal epithelium. Keratins provide mechanical strength but are involved in various regulatory functions of the cells. K8/K18 provide resistance to apoptosis on stress and injury, and this effect may be mediated through their effect on the death receptors (DR), Fas and TNF-a. K8/K18-null mouse hepatocytes were less resistant to Fas-mediated apoptosis [9]. Various abnormalities have been described in K8 deficient mice including colonic hyperplasia [10,11], hypersensitivity of the liver to stress [3,12], and alterations in intestinal epithelial membrane proteins [13]

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